Clinical Interpretation of genetic variants by ACMG/AMP 2015 guideline

InterVar is a bioinformatics software tool for clinical interpretation of genetic variants by the ACMG/AMP 2015 guideline. The input to InterVar is an annotated file generated from ANNOVAR, while the output of InterVar is the classification of variants into 'Benign', 'Likely benign', 'Uncertain significance', 'Likely pathogenic' and 'Pathogenic', together with detailed evidence code.

Please check/uncheck following criteria for your variant:

(If you has the position of your missense variant, you can clik here to search your variant.)

PVS1: null variant (nonsense, frameshift, canonical +- 2 splice sites, initiation codon, single or multiexon deletion) in a gene where LOF is a known mechanism of disease

PS1: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change
PS2: De novo (both maternity and paternity confirmed) in a patient with the disease and no family history
PS3: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product
PS4: The prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls
PS5: The user has additional strong pathogenic evidence

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
PM2: Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
PM3: For recessive disorders, detected in trans with a pathogenic variant
PM4: Protein length changes as a result of in-frame deletions/insertions in a nonrepeat region or stop-loss variants
PM5: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before
PM6: Assumed de novo, but without confirmation of paternity and maternity
PM7: The user has additional moderate pathogenic evidence

PP1: Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease
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
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)
PP4: Patient's phenotype or family history is highly specific for a disease with a single genetic etiology
PP5: Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation
PP6: The user has additional supporting pathogenic evidence

BA1: Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium

BS1: Allele frequency is greater than expected for disorder
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
BS3: Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing
BS4: Lack of segregation in affected members of a family
BS5: The user has additional strong benign evidence

BP1: Missense variant in a gene for which primarily truncating variants are known to cause disease
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
BP3: In-frame deletions/insertions in a repetitive region without a known function
BP4: Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
BP5: Variant found in a case with an alternate molecular basis for disease
BP6: Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
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
BP8: The user has additional supporting benign evidence