Criteria Specification Registry

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Criteria Specification

ClinGen Platelet Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ITGA2B Version 1.0.0

Description : This version specified for the following genes: ITGA2B, ITGB3

Version : 1.0.0

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Platelet Disorders VCEP

Released

6/12/2020

19:27:56

Rules for ITGA2B, ITGB3

Gene: ITGA2B (HGNC:6138) HGNC Name: integrin subunit alpha 2b Transcripts: NM_000419.4 Disease: Glanzmann thrombasthenia (MONDO:0010119)

Gene: ITGB3 (HGNC:6156) HGNC Name: integrin subunit beta 3 Transcripts: NM_000212.2 Disease: Glanzmann thrombasthenia (MONDO:0010119)

Criteria & Strength Specifications
PVS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Null variant (nonsense, frameshift, canonical +/−1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease. Caveats: • Beware of genes where LOF is not a known disease mechanism (e.g. GFAP, MYH7). • Use caution interpreting LOF variants at the extreme 3’ end of a gene. • Use caution with splice variants that are predicted to lead to exon skipping but leave the remainder of the protein intact. • Use caution in the presence of multiple transcripts. Stand Alone Very Strong Use decision tree as per SVI WG with specified “regions critical to protein function”. Strong Moderate Supporting Instructions: - In-frame exons: ITGA2B = 7, 8, 10, 12, 13, 15, 18, 21, 23, 25-30; ITGB3 = 6-9, 13, 15 - Regions “critical to protein function” have been specified to include: Extracellular domains involved in ligand binding: ITGB3 β1 domain, including amino acids 135-197 & 237-24 ITGA2B β Propeller domain (amino acids 32-482) The transmembrane domains of ITGA2B (amino acids 994-1019) and ITGB3 (amino acids (719-741) The cytoplasmic domain of ITGB3 (amino acids 742-788) Not Applicable
PS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong Use with no specification. Example: Val->Leu caused by either G>C or G>T in the same codon. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Moderate Supporting Not Applicable
PS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary De novo (both maternity and paternity confirmed) in a patient with the disease and no family history. Note: Confirmation of paternity only is insufficient. Egg donation, surrogate motherhood, errors in embryo transfer, etc. can contribute to non-maternity. Stand Alone Very Strong Use proposed SVI point recommendations. Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant. Strong Use proposed SVI point recommendations. Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant Use only when proband has an additional pathogenic or likely pathogenic variant with the de novo variant. Additionally, the P/LP variant must have been classified as such by the Platelet VCEP. Use ClinGen SVI’s proposed point recommendation table to determine the appropriate evidence code weight (see below). To be scored at the highest level with “Phenotype highly specific for gene” the proband must meet the PP4 criteria. Moderate Use proposed SVI point recommendations. Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant Supporting Use proposed SVI point recommendations. Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant Not Applicable
PS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. Note: Functional studies that have been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting are considered the most well-established. Stand Alone Very Strong Strong In a transgenic animal model, must demonstrate minimal to no function (flow cytometry JON/A, aggregation, or alternate assay analyzing integrin function) OR In a model organism or heterologous cell line, EITHER (A) when expression is normal or reduced (>5% expression compared to WT), disruption of protein function must be demonstrated by significantly reduced binding to fibrinogen or ligand mimetic antibodies (e.g. PAC-1) OR (B) Absent surface protein expression (<5% expression compared to WT) shown by at least 1 of 2 of the following assays: flow cytometry or Western blotting. Moderate In a model organism or heterologous cell line, significantly reduced surface protein expression (5-25% expression compared to WT) on at least 1 of 2 of the following assays: flow cytometry or Western blotting. Supporting Not Applicable
PS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0. See manuscript for detailed guidance. Note 2: In instances of very rare variants where case-control studies may not reach statistical significance, the prior observation of the variant in multiple unrelated patients with the same phenotype, and its absence in controls, may be used as moderate level of evidence. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: This rule does not apply to GT due to the rarity of this disorder and lack of appropriate studies. Additionally, most pathogenic variants are private (Nurden et al. Hum Mutat 2015; PMID: 25728920).
PM1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: This rule does not apply to GT due to the fact that these genes are thought to be highly polymorphic (PMID: 25827233); and there are no known hot spots.
PM2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Caveat: Population data for indels may be poorly called by next generation sequencing. Stand Alone Very Strong Strong Moderate Supporting Prevalence <1/10,000 (<0.0001) alleles in gnomAD. This evidence code is available when a variant is present in fewer than 1 in 10,000 alleles in the ExAC or gnomAD population cohorts. This cutoff was recommended based on work from Buitrago, et al showing that none of the established GT pathogenic variants were identified in ~32,000 alleles studies; suggesting that pathogenic variants have allele frequencies less than 0.01% in studied populations (PMID: 25827233) Not Applicable
PM3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary For recessive disorders, detected in trans with a pathogenic variant Note: This requires testing of parents (or offspring) to determine phase. Stand Alone Very Strong Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications. Strong Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications. Moderate Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications. Supporting Use proposed SVI point recommendations. Both variants must be classified using ITGA2B/ITGB3 Rule Specifications. Not Applicable
PM4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants. Stand Alone Very Strong Strong Moderate This rule can be applied as originally intended by the ACMG/AMP guidelines. Supporting Not Applicable
PM5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. Example: Arg156His is pathogenic; now you observe Arg156Cys. Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level. Stand Alone Very Strong Strong Moderate The strength of this rule may be adjusted based on the classification of the previously observed variant Supporting Use at adjusted strength. Novel missense change at an amino acid residue where a different missense change determined to be likely pathogenic has been seen before. Not Applicable
PM6 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Assumed de novo, but without confirmation of paternity and maternity. Stand Alone Very Strong Use proposed SVI point recommendations. Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant. Strong Use proposed SVI point recommendations. Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant Moderate Use proposed SVI point recommendations. Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant Use only when proband has a pathogenic or likely pathogenic variant in trans with the de novo variant. Use ClinGen SVI’s proposed point recommendation table to determine the appropriate evidence code weight (see PS2). To be scored at the highest level with “Phenotype highly specific for gene” the patient must meet the PP4 criteria. Supporting Use proposed SVI point recommendations. Only applicable when proband has a known pathogenic or likely pathogenic variant with the de novo variant Not Applicable
PP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. Note: May be used as stronger evidence with increasing segregation data. Stand Alone Very Strong Strong Segregations in proband plus >2 affected relatives. Affected relatives must have both variants identified in proband. Moderate Segregation in proband plus 2 affected relatives. Affected relatives must have both variants identified in proband. Supporting Segregation in proband plus 1 affected relative. Affected relatives must have both variants identified in proband. Not Applicable
PP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: This rule does not apply because benign missense variants are not rare. This rule does not apply to GT due to the fact that these genes are thought to be highly polymorphic (PMID: 25827233).
PP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm should not be counted as an independent criterion. PP3 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting REVEL score of > 0.7 OR >2 independent in silico missense predictors predict a damaging impact. For missense variants: REVEL score of > 0.7 is required for use of this rule code. Buitrago et al. (PNAS 2015) reported that three commonly used computational algorithms (Polyphen, SIFT, and CADD) to predict Pathogenicity had a 69–98% sensitivity in detecting GT pathogenic variants. (PMID: 25827233). For splicing variants: >2 independent in silico missense predictors predict a damaging impact We have used Human Splicing Finder and Maximum Entropy Scan with the following parameters: (1) the threshold for a position to be considered a splice site is >65 for HSF and >3 for MaxEntScan, (2) a broken splice site is defined as a position that has shifted below the threshold with a difference in score of <-10% for HSF or <-30% for MaxEntScan, and (3) a new splice site is defined as a position that has shifted above the threshold where the difference in score is >10% for HSF or >30% for MaxEntScan. Not Applicable
PP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology. Stand Alone Very Strong Strong Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities. Full sequencing of both genes is required at this strength Moderate Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities. Full sequencing of both genes is required at this strength. Supporting Proband with clinical diagnosis of GT based on the presence of mucocutaneous bleeding and appropriate lab abnormalities. Instructions: Proband must meet diagnostic criteria for GT, which includes phenotypic and laboratory finding PP4_Moderate & PP4 Bleeding phenotype: mucocutaneous bleeding including epistaxis, petichae, easy bruising, oral bleeding, gastrointestinal bleeding and menorrhagia (proband must have at least one bleeding symptom) PP4_Moderate Laboratory phenotype: Full sequencing of the ITGA2B and ITGB3 genes is required to use this code at a moderate weight. Abnormal lab values/patterns: (1) must demonstrate minimal to no aggregation with all, at least 2, tested agonists (except ristocetin, which must be normal) -AND- (2) EITHER (A) reduced (<25%) or absent surface protein expression (demonstrated by flow cytometry or Western blotting with patient cells) OR (B) functional flow cytometry of patient cells to demonstrate the inability of platelet binding to activated GPIIa/IIIa. PP4 Laboratory phenotype: Abnormal lab values/patterns: (1) must demonstrate minimal to no aggregation with all, at least 2, tested agonists (except ristocetin, which must be normal) Not Applicable
PP5
Original ACMG Summary Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BA1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium. Stand Alone Frequency cutoff of 0.24% (>0.0024 at 99.99% CI w/subpopulation w/min of 5 alleles). Very Strong Strong Moderate Supporting Not Applicable
BS1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Allele frequency is greater than expected for disorder. Stand Alone Very Strong Strong Frequency cutoff of 0.158% (>0.00158 at 99.99% CI w/subpopulation w/min of 5 alleles). Use a minor allele frequency cutoff of >0.00158 but <0.0024 (99.99% CI, sub-population must have a minimum of 5 alleles present in the sub-population) based on the Whiffen-Ware calculator. To set the strong MAF cutoff, we use the rationale discussed above and accounted for the two known genes associated with GT; whereas the above calculation assumed only one causative gene. Moderate Supporting Not Applicable
BS2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. Stand Alone Very Strong Strong >1 homozygote who is unaffected proven with at least aggregometry. This evidence code is available when the variant is identified in >1 homozygotes who are unaffected (proven with at least aggregometry). It is important to note that in order to use this rule one must have phenotypic information about an individual who is homozygous for a particular variant. This means one could not use population data (i.e. gnomAD or ExAC) as evidence. This code would more likely be used in the setting of gene panel testing, where an individual with a different phenotype was found to be homozygous for a variant in one of those two genes. Moderate Supporting Not Applicable
BS3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing. Stand Alone Very Strong Strong Must demonstrate normal aggregometry in a transgenic mouse model. OR In a heterologous cell line, must demonstrate BOTH normal expression and normal protein function. Moderate Supporting Not Applicable
BS4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Lack of segregation in affected members of a family. Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals. Also, families may have more than one pathogenic variant contributing to an autosomal dominant disorder, further confounding an apparent lack of segregation. Stand Alone Very Strong Strong Variant not detected in an affected family member. Moderate Supporting Not Applicable
BP1 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Missense variant in a gene for which primarily truncating variants are known to cause disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Rule does not apply as truncating variants do not predominate and missense variants are a known cause of disease.
BP2 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. Stand Alone Very Strong Strong Moderate Supporting Use as written for recessive variants (i.e. - variant must be observed in cis with a pathogenic variant) Not Applicable
BP3 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary In frame-deletions/insertions in a repetitive region without a known function. Stand Alone Very Strong Strong Moderate Supporting This rule can be applied as originally intended by the ACMG/AMP guidelines in the ITG3B gene, which has three repetitive microsatellite regions. There are no known repetitive regions in the ITGA2B gene. Not Applicable
BP4 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) Caveat: As many in silico algorithms use the same or very similar input for their predictions, each algorithm cannot be counted as an independent criterion. BP4 can be used only once in any evaluation of a variant. Stand Alone Very Strong Strong Moderate Supporting REVEL score of < 0.25. Use this code for missense variants with a REVEL score of < 0.25. ● This recommendation was based on evaluating the REVEL scores of variants assessed as benign by this VCEP using our rule specifications with the exception of this rule code. All benign and likely benign variants fell under this threshold. ● We are not recommending the use of other missense in silico model predictors at this time due to a previous concern about their validity for these genes as demonstrated by Buitrago et al. (PNAS 2015). They found that the three computational algorithms they used were less reliable predicting non-pathogenicity of previously known benign variants. (PMID: 25827233) Not Applicable
BP5 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary Variant found in a case with an alternate molecular basis for disease. Stand Alone Very Strong Strong Moderate Supporting Not Applicable Comments: Diminished platelet expression and function of αIIB β3 integrin is very specific for GT. Therefore, pathogenic variants in other genes (such as FERMT2 and RASGRP2) are subtypes of GT in which there is only diminished function of αIIB β3 integrin may have similar laboratory features to other platelet disorders. In these cases, pathogenic variants in other platelet genes may be causative.
BP6
Original ACMG Summary Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. Not Applicable This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. PubMed : 29543229
BP7 PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7 Files References
Original ACMG Summary A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved. Stand Alone Very Strong Strong Moderate Supporting Use with no specification. This rule can be applied as originally intended by the ACMG/AMP guidelines. Not Applicable

Rules for Combining Criteria

Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong, PM6_Very Strong) AND ≥ 1 Strong (PS1, PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong, PP4_Strong)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong, PM6_Very Strong) AND ≥ 2 Moderate (PS2_Moderate, PS3_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong, PM6_Very Strong) AND 1 Moderate (PS2_Moderate, PS3_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate) AND 1 Supporting (PS2_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong, PM6_Very Strong) AND ≥ 2 Supporting (PS2_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

≥ 2 Strong (PS1, PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong, PP4_Strong)

1 Strong (PS1, PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong, PP4_Strong) AND ≥ 3 Moderate (PS2_Moderate, PS3_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate)

1 Strong (PS1, PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong, PP4_Strong) AND 2 Moderate (PS2_Moderate, PS3_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PS2_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Strong (PS1, PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong, PP4_Strong) AND 1 Moderate (PS2_Moderate, PS3_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PS2_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

Likely Pathogenic

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong, PM6_Very Strong) AND 1 Moderate (PS2_Moderate, PS3_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate)

1 Strong (PS1, PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong, PP4_Strong) AND 1 Moderate (PS2_Moderate, PS3_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate)

1 Strong (PS1, PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong, PP4_Strong) AND ≥ 2 Supporting (PS2_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

≥ 3 Moderate (PS2_Moderate, PS3_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate)

2 Moderate (PS2_Moderate, PS3_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate) AND ≥ 2 Supporting (PS2_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Moderate (PS2_Moderate, PS3_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate) AND ≥ 4 Supporting (PS2_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

1 Strong (PS1, PS2, PS3, PM3_Strong, PM6_Strong, PP1_Strong, PP4_Strong) AND 2 Moderate (PS2_Moderate, PS3_Moderate, PM3, PM4, PM5, PM6, PP1_Moderate, PP4_Moderate)

1 Very Strong (PVS1, PS2_Very Strong, PM3_Very Strong, PM6_Very Strong) AND 1 Supporting (PS2_Supporting, PM2_Supporting, PM3_Supporting, PM5_Supporting, PM6_Supporting, PP1, PP3, PP4)

Benign

≥ 2 Strong (BS1, BS2, BS3, BS4)

1 Stand Alone (BA1)

Likely Benign

1 Strong (BS1, BS2, BS3, BS4) AND 1 Supporting (BP2, BP3, BP4, BP7)

≥ 2 Supporting (BP2, BP3, BP4, BP7)