SNOWPLE

ACMG 가이드라인

논문도 있고, 사이트도 참조(http://www.genomize.com/blog/content/ngs.html)

아래와 같이 변이에 대해 Evidence Level을 분류한다.

PVS1:Null variant (nonsense, frameshift, canonical ± 1 or splice sites, initiation codon, single or multiexon deletion )

PS1:Same aa change as previously established pathogenic variant regardless of nucleotide change

PS2:De novo in a patient with the disease and no family history

PS3:In vitro or in vivo functional studies supportive of a damaging effect

PS4:Prevelance of the variant is significantly increased in affected individuals than in unaffected

PM1:Located in a mutation hotspot and/or functional domain without benign variation

PM2:Low allele frequency

PM3:In trans with a pathogenic variant (for recessive disorders)

PM4:Protein length changes as a result

PM5:Novel missense change at a aa where a different missense has been determined pathogenic before

PM6:Assumed de novo (witghout confirmation od paternity of maternity)

PP1:Cosegregation with disease in multiple affected family members in the disease causing gene

PP2:Missense variant in a gene with low rate of benign variation

PP3:Computational evidence reports pathogenic (sift, polyphen)

PP4:Phenotype of family history highly specific

PP5:Reputable resource reports pathogenic (clinvar)

BA1:Very high allele frequency

BS1:Allele frequency greater than expected for the disorder

BS2:Observed in a healthy adult for a disease with full penetrance expected at an early age

BS3:In vitro or in vivo functional studies supportive of no damaging effect

BS4:Lack of segregation in affected family members

BP1:Missense variant in a disorders where truncating variants are known to cause disease

BP2:Observed in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritence

BP3:In-frame deletion/insertion in a repetitive region

BP4:Computational evidence reports benign (sift, polyphen)

BP5:Existent in a case with an alternate molecular basis for the disease

BP6:Reputable resource reports benign (clinvar)

BP7:Synonymous variation predicted to have no impact on splicing

변이별 분류된 Evidence Level을 기반으로 Pathogenic 유무를 구분한다.

Pathogenic (P)

(i) 1 Very strong (PVS1) AND

(a) ≥1 Strong (PS1–PS4) OR

(b) ≥2 Moderate (PM1–PM6) OR

(c) 1 Moderate (PM1–PM6) and 1 supporting (PP1–PP5) OR

(d) ≥2 Supporting (PP1–PP5)

(ii) ≥2 Strong (PS1–PS4) OR

(iii) 1 Strong (PS1–PS4) AND

(a) ≥3 Moderate (PM1–PM6) OR

(b) 2 Moderate (PM1–PM6) AND ≥2 Supporting (PP1–PP5) OR

(c) 1 Moderate (PM1–PM6) AND ≥4 supporting (PP1–PP5)

Likely pathogenic (LP)

(i) 1 Very strong (PVS1) AND 1 moderate (PM1–PM6) OR

(ii) 1 Strong (PS1–PS4) AND 1–2 moderate (PM1–PM6) OR

(iii) 1 Strong (PS1–PS4) AND ≥2 supporting (PP1–PP5) OR

(iv) ≥3 Moderate (PM1–PM6) OR

(v) 2 Moderate (PM1–PM6) AND ≥2 supporting (PP1–PP5) OR

(vi) 1 Moderate (PM1–PM6) AND ≥4 supporting (PP1–PP5)

Benign (B)

(I) 1 Stand-alone (BA1) OR

(ii) ≥2 Strong (BS1–BS4)

Likely benign (LB)

(i) 1 Strong (BS1–BS4) and 1 supporting (BP1–BP7) OR

(ii) ≥2 Supporting (BP1–BP7)

Uncertain significance (VUS)

(i) Other criteria shown above are not met OR

(ii) the criteria for benign and pathogenic are contradictory

*Pathogenic with Family Segregation Data (PF)

(i) PM2 AND PP3 OR

(ii) PM2 AND PM4