Table 3.
Evidence that Identified Germline and Somatic Mutations Result in LoF
| Sample ID | Germline Mutation | Somatic Mutation |
|---|---|---|
| 6001-1 | frameshift: ACMG PVS1 6 supporting publications |
in-frame deletion (−4 residues) PROVEAN prediction: deleterious (−14.903) deletes region in β-sheet gnomAD AF: 0 |
| 6001-3 | same as above | frameshift common ENG LOF mechanism, expect NMD |
| 6001-7 | same as above | frameshift common ENG LOF mechanism, expect NMD |
| 6001-8 | same as above | in-frame delins (−1 +2 residues) 2 reported pathogenic in-frame indels overlapping this codon54, 55 PROVEAN prediction: deleterious (−6.106) gnomAD AF: 0 |
| 6001-10 | same as above | frameshift common ENG LOF mechanism, expect NMD |
| 6002-1 | missense: ACMG PS1 6 supporting publications |
frameshift common ACVRL1 LOF mechanism, expect NMD |
| 6002-2 | same as above | in-frame delins (−7 +1 residues) PROVEAN prediction: deleterious (−25.903) deletes region in α-helix gnomAD AF: 0 |
| 6003-1 | cryptic splice site: ACMG PS3 in silico predicted to activate cryptic site in vitro evidence (Fig. 4) |
Splice Site in silico predicted to disrupt donor site gnomAD AF: 0 |
| 6005-1 | missense: ACMG PS1 16 supporting publications |
Frameshift common ACVRL1 LOF mechanism, expect NMD |
AF = Allele Frequency; NMD = Nonsense Mediated Decay
Germline variant classification according to ACMG guidelines, not applicable to somatic variants31
PVS1 = Very strong evidence for pathogenicity; PS1-4 = Strong evidence
PROVEAN scores below −2.5 are predicted deleterious