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bAyesCMG

An applied Bayesian framework for the ACMG/AMP criteria

Purpose

Applying the ACMG/AMP criteria often is tedious, manual and subject to human error. bAyesCMG provides automated application of pathogenic and benign ACMG/AMP evidence codes to all variant records in a given VCF file. bAyesCMG then uses these evidence codes to assign a Bayesian posterior probability of pathogenicity (0 to 1 scale), according to Tavtigian et al, 2018, for downstream filtering and variant review. bAyesCMG dramatically reduces the number of variants for consideration in Mendelian disease studies and is capable of correctly prioritizing the diagnostic variant in whole exome and whole genome sequencing data.

Installation

Usage

Requires:

  1. a multi-sample merged (preferably joint called) VCF with three samples: proband, mom, dad - pre-processing this VCF is recommended, normalizing, decomposing and annotating with VEP
  2. a pedigree file describing the relatedness between the VCF samples

Flags

Output

Assertions:

-1 == evidence code evaluated, NEGATIVE assertion
0 == evidence code NOT evaludated
1 == evidence code evaluated, POSITIVE assertion

Filtering

Evidence Codes

Evidence Code and Descrption Implementation Description
PVS1 "Null variant (nonsense, frameshift, canonical ±1 or 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease" VEP IMPACT field is HIGH, gene with known LOF mechanism is not considered
PS1 "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change" Same amino acid change as annotated pathogenic variant in ClinVar VCF, disease/phenotype not considered
PS2 "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history" Genotype 0/1 in proband, genotypes 0/0 in both parents
PS3 "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product" Not currently implemented
PS4 "The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls" Genotype segregates with affected status, regardless of genotype, 0/1 in proband and 0/0 in both parents, or 1/1 in proband and 0/0 or 0/1 in parents
PM1 "Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation" Variant has a functional domain annotation in VEP --domains field
PM2 "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium" Less than 0.01 frequency in gnomAD (default), can also be specified by user
PM3 "For recessive disorders, detected in trans with a pathogenic variant" Not currently implemented
PM4 "Protein length changes as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants" VEP Consequence field is inframe_insertion, inframe_deletion or stop_lost, currently not considering repeat regions or surrounding bases
PM5 "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before" Where ClinVar VCF CLNSIG is Pathogenic, given variant VEP Protein_position matches ClinVar variant, but Amino_acids does not match
PM6 "Assumed de novo, but without confirmation of paternity and maternity" Not currently implemented, requiring trios
PP1 "Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease" Not currently implemented, requiring trios, not quartets or larger with multiple affected individuals
PP2 "Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease" Not currently implemented
PP3 "Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)" VEP REVEL plugin score greater than 0.6 (default) or a user-specified value
PP4 "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology" Not currently implemented
PP5 "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation" Not currently implemented
BA1 "Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium" gnomAD population max allele frequency is greater than 0.05
BS1 "Allele frequency is greater than expected for disorder" gnomAD population max allele frequency is greater than 0.01 (default) or user-specified value
BS2 "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" Variant does not segregate with affected status, for 1/1 (hom-alt), 1/1 genotype also in an unaffected parent, for 0/1 (het), 0/1 genotype also in an unaffected parent
BS3 "Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing" Not currently implemented
BS4 "Lack of segregation in affected members of a family" Variant does not segregate with affected status, for 1/1 (hom-alt), 1/1 genotype also in an unaffected parent, for 0/1 (het), 0/1 genotype also in an unaffected parent
BP1 "Missense variant in a gene for which primarily truncating variants are known to cause disease" Not currently implemented
BP2 "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" Not currently implemented
BP3 "In-frame deletions/insertions in a repetitive region without a known function" No VEP DOMAINS field and Consequence field is inframe_insertion, inframe_deletion or stop_lost, currently not considering repeat regions or surrounding bases
BP4 "Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)" VEP REVEL plugin score less than 0.6 (default) or a user-specified value
BP5 "Variant found in a case with an alternate molecular basis for disease" Not currently implemented
BP6 "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation" Not currently implemented
BP7 "A synonymous (silent) 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" VEP Consequence is synonymous and not splice_region, or annotated from SpliceRegion plugin

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