Table 2 Criteria for the classification of benign variants.
From: Correction: Interpretation of mitochondrial tRNA variants
Evidence | ACMG criteria | Criteria for mt-tRNA variants |
|---|---|---|
Stand-alone | BA1 Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes, or ExAC. | BA1 Top-level haplogroup defining variants. |
Strong | BS1 Allele frequency is greater than expected for disorder. | BS1 Reported in public databases (e.g., MitoMap or mtDB) or literatures as polymorphism. |
BS2 Observed in healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder with full penetrance expected at an early age. | BS2 Found homoplasmic in more than three unrelated healthy adults. | |
BS3 Well-established in vitro or in vivo functional studies shows no damaging effect on protein function or splicing. | BS3 Not applicable. | |
BS4 Lack of segregation in affected members of a family. | BS4 Homoplasmy in both probands and at least 2 asymptomatic matrilineal family members. | |
Supporting | BP1 Missense variant in a gene for which primarily truncating variants are known to cause disease. | BP1 Not applicable. |
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. | BP2 Not applicable. | |
BP3 In-frame deletions/insertions in a repetitive region without a known function. | BP3 Not applicable. | |
BP4 Multiple lines of computational evidence suggest no impact on gene or gene product. | BP4 The MitoTIP prediction score is <10. | |
BP5 Variant found in a case with an alternate molecular basis for disease. | BP5 In the presence of a known pathogenic genetic cause unless there is evidence of more than one disease and clinically explained. | |
BP6 Reputable source recently reports variant as benign but the evidence is not available to the laboratory to perform an independent evaluation. | BP6 Found to be homoplasmic more than once in asymptomatic adults in private reputable laboratory databases. | |
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. | BP7 Not applicable. |
