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Rule | Category | Rule description |
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Evidence of pathogenic |
Very strong | PVS1 | Null variants which caused loss of function are known to be the mechanism of diseases. |
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Strong | PS1 | Different nucleotide change caused same amino acid change with known pathogenic variants. |
PS2 | De novo (confirmed maternity and paternity) in a patient with no family history and diseases. |
PS3 | Functional studies supported the effect of related pathogenic variants. |
PS4 | Variants’ prevalence significantly increased in affected individuals than controls. |
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Moderate | PM1 | Mutation happened in hot spot and known function domain. |
PM2 | Absent (or extremely low) in large population studies. |
PM3 | With recessive disease, detected in trans with pathogenic variants. |
PM4 | Variants (in-frame deletions/insertions in a nonrepeat region or stop-loss variants) lead to changes in protein length. |
PM5 | Different missense changes at known pathogenic amino acid residue. |
PM6 | De novo (without confirmation of maternity and paternity). |
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Supporting | PP1 | Variants known to be the causes affected multiple family members. |
PP2 | Missense variants in a gene that have a low rate of benign missense variation are common mechanism of disease. |
PP3 | Multiple lines of computational evidence support a deleterious effect on the gene or gene products. |
PP4 | Phenotype specific for disease with single genetic etiology. |
PP5 | Reputable source reports variants as pathogenic. |
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Evidence of benign |
Stand-alone | BA1 | Allele frequency is >0.5% base on population database. |
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Strong | BS1 | Allele frequency is greater than expected for disorder. |
BS2 | Recessive heredity being observed in healthy adult. |
BS3 | Functional studies show no pathogenic effect. |
BS4 | Without segregation. |
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Supporting | BP1 | Missense variant in gene where only loss of function is pathogenic. |
BP2 | Observed in genes with overlapping function without increased disease severity or observed in cis with a pathogenic variant. |
BP3 | Variants (in-frame deletions/insertions in a nonrepeat region or stop-loss variants) lead to changes in a repetitive region without known function. |
BP4 | Multiple lines of computational evidence suggest no impact on gene or gene product. |
BP5 | Variant found in a case with alternate molecular basis for disease. |
BP6 | Report as benign. |
BP7 | Splicing variant predict an algorithm which predict no impact to the splice consensus sequence. |
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