Table 5 Comparison of ACMG and ABC classification in dominant (cases 1–6), recessive (cases 7–11), and SNP-array (cases 12–16) settings.
From: Stepwise ABC system for classification of any type of genetic variant
Case# | Gene/CNV | Finding | Clinical information | ACMG class calculationa | ABC | ACMG class vs ABC class |
|---|---|---|---|---|---|---|
1 | F5 | NM_000130.4:c.1601G > A p.Arg534Gln MAF 0.04–0.07 (Europeans) | A: unexpected deep venous thrombosis at age 56 | VUS (PS3, PS4, PP1, BA1) | D/5 + 2 | VUS D—susceptibility variant |
2 | JAK2 | NM_004972.3:c.2048_2050del p.(Arg683_Glu684insLys) Not in gnomAD v2.1.1 | A: high platelet counts, dominant trait in healthy asymptomatic family members | LP (PS4, PP1-M, PM2, PP4) | E/4 + 1 | LP E—potential interest variant |
3 | UMOD | NM_001278614.1:c.915C > A p.(Tyr305a) Not in gnomAD v2.1.1 | B: incidental finding in neonate with cyanosis, unknown if variant is inherited | VUS (PM2, PP3) | E/5 + 0 | VUS E—no explanation found |
4 | BICD2 | NM_015250.3:c.793A > G p.(Met265Val) 8 in gnomAD v2.1.1 | A: family with dominant drop-foot tendency, areflexia and thenar atrophy | VUS (PP1-M, PP3, BS1) | E/3 + 1 | VUS E—potential interest variant |
5 | BRCA2 | LRG_293t1:c.8177A > G p.(Tyr2726Cys) Not in gnomAD v.2.1.1 | A: siblings with ca. ovarii, decreased repair function found in one study | LP (PS4, PM2, PP3, BP1) | D/4 + 2 | LP D—susceptibility variant |
6 | CACNA1C | NM_000719.6:c.5852C > G p.(Pro1951Arg) de novo Not in gnomAD v.2.1.1 | A: ID with autism, hypospadias and dysmorphic facial features | LP (PS2, PM2, PP2) | E/3 + 2 | LP E—no explanation found |
7 | FECH | Chr18(GRCh38):g.5757571588A > G NM_000140.3:c.315-48T > C r.314_315ins315-49_315-1 MAF 0.11 in gnomAD v.2.1.1 | A: erythropoietic protoporphyria (EPP), only one variant found | VUS (PS3, PS4, PP1-S, PM3, PP4, BA1) | D/4 + 2 | VUS D—potential interest variant |
8 | C3 | LRG_27t1:c.4893G > A p.(Trp1631a) from father Not in gnomAD v.2.1.1 | A: atypical hemolytic uremic syndrome. Only case in family, both parents no signs of aHUS. Five healthy relatives carry the paternal variant in the last exon of C3, and three healthy relatives carry the maternal missense variant. | LP (PS3, PM2, PP3, BS2) | D/4 + 2 | LP D—susceptibility variant |
C3 | LRG_27t1:c.2203C > T p.(Arg735Trp) from mother Not in gnomAD v.2.1.1 | VUS (PM2, PP3, BS2) | E/3 + 2 | VUS E—potential interest variant | ||
C3 | LRG_27t1:c.3346G > A p.(Gly1116Arg) from mother MAF 0.002 in gnomAD v.2.1.1 | LB (BP4, BS1) | F/2 + 0 | LB F—not further classified | ||
9 | FLVCR2 | NM_017791.2:c.615G > T p.(Trp205Cys) homozygous 1 in gnomAD v.2.1.1 | A: aborted fetus with hydranencephaly and cerebral vasculopathy (Fowler syndrome) | VUS (PM2, PP3, PP4) | C/3 + 5 | VUS C—pathogenic |
10 | CFTR | NM_000492.3:c.1521_1523del p.(Phe508del) heterozygous | B: aortic aneurysm in young adult | P (PS1, PS3, BS2?) | E/5 + 0 | P (incidental finding) E—no explanation found |
11 | CFTR | NM_000492.3:c.1521_1523del p.(Phe508del) heterozygous | A: nasal polyps in young adult | P (PS1, PS3, PS4) | D/5 + 2 | PD—susceptibility variant |
12 | Dup GRIA3 | NC_000023.10:g.(123183157 _?)_(?_123704413)dup, unknown if dup on X is de novo | A: boy with learning problems and epilepsy | VUS, score 0.30? | E/3 + 1 | VUS E—potential interest CNV |
13 | Del 15q13.3 | Classic deletion (from BP4 to BP5) | Learning problems, psychosis | P, score 1.00 | B/5 + 4 | P B—pathogenic |
14 | Dup 15q13.3 | Classic duplication (from BP4 to BP5) | Learning problems | VUS, score <0.45 | D/4 + 2 | VUS D—potential interest CNV |
15 | Genome | ~10% of aut. genome is IBD | Fetus with occipital encephalocele and postaxial polydactyly | NA | E/3 + 2 | E—potential interest ROH |
16 | Genome | ~10% of aut. genome is IBD | Fetus with normal ultrasound findings | NA | F/3 + 0 | F—normal finding |
