Table 4.
Cases with variants of interest classified as variants of uncertain significance or in genes of uncertain significance
| ID | Variant | Allele frequency | In silico prediction | Previous report | ACMG-AMP classification | ||||
|---|---|---|---|---|---|---|---|---|---|
| gnomADa | ABraOM | SIFTb | PP2c | GERP++d | CADDpe | ||||
| 1 | PTDSS1 p.(Gly72Ser) | 0.0017 (NFE) | 0.0016 | D | D | 5.54 | 28 | No | NA (GUS) |
| 2 | COLEC10 p.(Arg125Trp) | 0.0011 (ASJ) | 0.0000 | D | D | 4.1 | 21.8 | No | NA (GUS) |
| 3 | COL1A1 p.(Arg528His) | 0.0012 (ASJ) | 0.0008 | D | D | 5.06 | 17.2 | ClinVar | VUS |
| WLS p.(Gln25His) | 0.0011 (LAT) | 0.0008 | D | D | –2.39 | 16.3 | No | NA (GUS) | |
| WNT1 p.(Cys93Tyr) | 0.0000 | 0.0000 | D | D | 5.04 | 24.7 | No | VUS | |
| 5 | P3H1 p.(Pro358Thr) | < 0.0001 (LAT) | 0.0000 | D | P | 5.84 | 15.2 | No | VUS |
| 6 | GPR68 exonic deletion | NA | NA | NA | NA | NA | NA | No | NA (GUS) |
| 7 | NBR1 p.(Gly759Val) | 0.0001 (NFE) | 0.0000 | D | D | 5.64 | 25.8 | No | NA (GUS) |
| 10 | CCDC170 p.(Glu451Lys) | 0.0025 (AFR) | 0.0000 | D | D | 1.21 | 33 | No | NA (GUS) |
| 11 | LACTB2 p.(144_147del)f | 0.0051 (NFE) | 0.0057 | NA | NA | NA | NA | No | NA (GUS) |
| NOTCH2 p.(Leu2408His)f | 0.0032 (NFE) | 0.0074 | D | D | 5.35 | 25.5 | ClinVar | VUS | |
| 12 | PKDCC p.(Asn210Lys) | 0.0000 | 0.0000 | D | D | 3.12 | 33 | No | NA (GUS) |
| 13 | PLS3 p.(Arg94Cys) | 0.0000 | 0.0020 | D | D | 4.00 | 34 | No | VUS |
| 17 | AXIN1 p.(Val683Met) | < 0.0001 (SAS) | 0.0000 | T | D | 2.18 | 22.7 | No | NA (GUS) |
| 19 | NBR1 p.(Asp40Gly) | 0.0000 | 0.0000 | T | D | 5.26 | 23.5 | No | NA (GUS) |
| 20 | USF3 p.(Ser1425Leu) | 0.0005 (LAT) | 0.0000 | D | B | 5.06 | 22.3 | No | NA (GUS) |
| 21 | LACTB2 p.(144_147del)f | 0.0051 (NFE) | 0.0057 | NA | NA | NA | NA | No | NA (GUS) |
| F2 | GALNT3 p.(Lys347Thr) | 0.0000 | 0.0000 | T | B | 4.41 | 18.5 | No | NA (GUS) |
| WNT1 p.(Thr336Met) | 0.0093 (AFR) | 0.0017 | D | D | 3.5 | 19.6 | No | VUS | |
| F3 | BMP1 p.(Arg371His) | 0.0062 (NFE) | 0.0066 | T | D | 5.77 | 26.4 | ClinVar | VUS |
| F5 | ANAPC1 p.(Val1052Met) | 0.0001 (LAT) | 0.0000 | D | B | 4.58 | 24.1 | No | NA (GUS) |
Abbreviations: ACMG-AMP, American College of Medical Genetics and Genomics and the Association for Molecular Pathology; CADD, combined annotation–dependent depletion; GERP, genome evolutionary rate profiling; GUS, genes of uncertain significance; ID, identification; SIFT, Sorting Intolerant From Tolerant; VUS, variants of uncertain significance.
aHighest ethnicity-specific minor allele frequencies are reported (AFR, African; ASJ, Ashkenazi Jewish; LAT, Latino; NFE, Non-Finnish European; SAS, South Asian).
bSIFT output prediction: D, damaging; T, tolerated.
cPolyPhen2 HumDiv prediction: B, benign; D, probably damaging; P, possibly damaging.
dGERP++ rejected substitutions (RS) score (a suggested threshold for deleteriousness is > 4.4).
ePHRED-like scaled C-score according to the CADD framework (a suggested threshold for deleteriousness is > 15); ABraOM, Online Archive of Brazilian Mutations; gnomAD, Genome Aggregation Database; NA, not applicable.
fRecurring variants.