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.
Status
Implemented
Resources
LoF genes list from intervar. https://raw.githubusercontent.com/barslmn/InterVar/master/intervardb/PVS1.LOF.genes.hg19
Null variants defined as HIGH IMPACT by https://www.ensembl.org/info/genome/variation/prediction/predicted_data.html
Conditions
"gene_symbol" is in LoF gene list.
"transcript_consequence_terms" is high impact.
Shortcomings
LoF gene list is only predictive and may be missing some actual LoF genes.
No checks for multiexon deletion.
PS1
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Status
Implemented
Resources
Clinvar xml (ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/)
Annotation Steps
Clinvar data is parsed using https://github.com/barslmn/clinvar.
Sample data and clinvar data is merged based on columns "CHR" and "POS".
Clinvar feature columns "ALT", "hgvsp", and "clinical_significance" added to original annotation.
Conditions
"clinical_significance" is pathogenic.
Sample "hgvsp" and later added clinvar "hgvsp" changes are the same.
Sample "ALT" and clinvar "ALT" are different.
Shortcomings
PS2
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
Status
Not Checked
Resources
Conditions
Shortcomings
PS3
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product
Status
Not Checked
Resources
Conditions
Shortcomings
PS4
The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls
Status
Implemented
Resources
Intervar
Conditions
"id" is in id list.
Shortcomings
No idea how the source is made.
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
Status
Planned.
Resources
Conditions
Shortcomings
PM2
Absent from controls (or at extremely low frequency if recessive) (Table 6) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Status
Implemented
Resources
VEP
Conditions
"gnomad" less than 0.001.
Shortcomings
PM3
For recessive disorders, detected in trans with a pathogenic variant
Status
Planned for trio
Resources
Conditions
Shortcomings
PM4
Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
Status
Implemented
Resources
VEP
Conditions
"transcript_consequence_terms" is "inframe_insertion", "inframe_deletion", or "stop_lost".
Shortcomings
No checks for repeat regions.
PM5
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
Status
Broken. (╯°□°）╯︵ ┻━┻)
Resources
Clinvar xml (ftp://ftp.ncbi.nlm.nih.gov/pub/clinvar/)
Annotation Steps
Clinvar data is parsed using https://github.com/barslmn/clinvar.
Sample data and clinvar data hgvsp columns parsed till position.
Synonym changes removed from clinvar data.
Clinvar feature columns "hgvsc", and "clinical_significance" added to original annotation based on protein change position.
Conditions
"gnomad" less then 0.001.
"clinical_significance" is pathogenic.
"transcript_consequence_terms" is missense variant.
"hgvsc" of the variant and clinvar entry dont match.
Shortcomings
PM6
Assumed de novo, but without confirmation of paternity and maternity
Status
Planned for trio.
Resources
Conditions
Shortcomings
PP1
Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease
Status
Not Checked.
Resources
Conditions
Shortcomings
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
Status
Implemented
Resources
Intervar
Conditions
"transcript_consequence_terms" is a missense variant.
"gene_symbol" is in PP2 gene list.
Shortcomings
PP3
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
Status
Implemented
Resources
Vep
Conditions
"sift_score" less than 0.05
"polyphen_score" greater than 0.908
Shortcomings
PP4
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology
Status
Not Checked.
Resources
Conditions
Shortcomings
PP5
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
Status
Implemented.
Resources
Clinvar
Conditions
"clinical_significance" is Pathogenic.
Shortcomings
Benign
BA1
Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Status
Implemented.
Resources
Vep
Conditions
"minor_allele_freq" is greater than 0.05
OR
"gnomad" is greater than 0.05.
Shortcomings
BS1
Allele frequency is greater than expected for disorder
Status
Planned for later.
Resources
Conditions
Shortcomings
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
Status
Planned
Resources
Intervar
Conditions
Shortcomings
BS3
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing
Status
Not Checked.
Resources
Conditions
Shortcomings
BS4
Lack of segregation in affected members of a family
Status
Not Checked.
Resources
Conditions
Shortcomings
BP1
Missense variant in a gene for which primarily truncating variants are known to cause disease
Status
Implemented.
Resources
Intervar
Conditions
"transcript_consequence_terms" is a missense variant.
"gene_symbol" is in BP1 gene list.
Shortcomings
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
Status
Planned for trio.
Resources
Conditions
Shortcomings
BP3
In-frame deletions/insertions in a repetitive region without a known function
Status
Planned.
Resources
Conditions
Shortcomings
BP4
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Status
Implemented
Resources
VEP
Conditions
"sift_score" greater than or equals to 0.05
"polyphen_score" less than or equals to 0.446
Shortcomings
BP5
Variant found in a case with an alternate molecular basis for disease
Status
Not Checked.
Resources
Conditions
Shortcomings
BP6
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Status
Implemented
Resources
Clinvar
Conditions
"clinical_significance" is benign
Shortcomings
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