TABLE 3.
Variants in genes associated with microphthalmia, anophthalmia and coloboma (MAC)
| Sample | Gene name | Human genome variation society (HGVS) nomenclature | Zygosity | gnomAD minor allele frequency | Polyphen-2 | Mutation Taster | CADD scorea | Conservation | ACMG Classification6 |
|---|---|---|---|---|---|---|---|---|---|
| pathogenic/likely pathogenic variants | |||||||||
| EG16_1 | TENM3 chr4:183601421C>T | NM_001080477.4: c.1558C>T: p.(Arg520*) | Homozygous; biparental | Absent | – | DCb; 1.0 | 38 | – | Pc (PVS1, PM2, PP3) |
| EG25_1 | POLR2A chr17:7406570C>T | NM_00937.4: c.2887C>T: p.(Arg963Trp) | Heterozygous; de novo | Absent | Prob. Dd; 1.0 | DC; 0.999 | 27.7 | Pte/Mmusf/Drg/Dmh/Cei/Xtj | LPk (PM2; PS2, PP3) |
| Variants of unknown significance | |||||||||
| EG22_1 | WNT2B chr1:113059863C>T | NM_024494.3: c.802C>T: p.(Arg268Cys) | Heterozygous; maternal | 10/251396 No Hzl | Prob. D; 0.999 | DC; 0.999 | 33 | Pt/Mmm/Fcn/Mmus | VUSo (PP3) |
| EG41_1 | DHX37 chr12:125438446C>T | NM_032656.3: c.2675G>A: p.(Arg892Gln) | Heterozygous; paternal | 5/241454 No HZ | Prob. D; 1.0 | DC; 0.999 | 32 | Mm/Fc/Mmus/Ggp/Trq/Dr/Dm/Ce | VUS (PP3) |
| EG38_1 | KIF26B chr1:245847561G>A | NM_018012:c.2285G>A: p.(Arg762Gln) | Homozygous; biparental | 5/248968 No HZc | Prob. Dd; 0.976 | DC; 0.999 | 31 | Pte/Mmusf/Ggg/Trh/Dri/CeVXtk | VUS (PM2, PP3) |
| EG40_1 | MICU1 chr10:74234905A>C | NM_001195518.2: c.886 T>G: p.(Phe296Val) | Homozygous; biparental | Absent | Prob. D; 1.0 | DC; 0.999 | 29.5 | Pt/Mml/Fcm/Mmus/Gg/Tr/Dr/Dmn/Ce/Xt | VUS (PM2, PP3) |
| EG41_1 | ADAMTS9 chr3:64536590C>A | NM_182920.1: c.4847G>T: p.(Trp1616Leu) | Heterozygous; maternal | 2/251360 No HZ | Prob. D; 0.989 | DC; 0.999 | 29.5 | Pt/Mm/Mmus/Gg/Dr/Ce/Xt | VUS (PP3) |
| EG28_1 | LRP6 chr12:12334319G>A | NM_002336.3: c.1031 T>C: p.(Leu344Ser) | Heterozygous; paternal | Absent | Prob. D; 1.0 | DC; 1.0 | 28.8 | Pt/Mm/Mmus/Gg/Dr/Dm/Xt | VUS (PM2, PP3) |
| EG25_1 | WFS1 chr4:6303728G>A | NM_00114853: c.2206G>A: p.(Gly736Ser) | Heterozygous; paternal | 8/245860 No HZ | Prob. D; 1.0 | DC; 0.999 | 28.7 | Mm/Fc/Mmus/Dr/Dm/Xt | VUS (PP3) |
| EG15_1 | RERE chr1:8418508G>A | NM_012102.3: c.4087C>T: p.(Pro1363Ser) | Heterozygous; paternal | Absent | Prob. D; 0.969 | DC; 1.0 | 26.2 | Pt/Mm/Fc/Mmus/Gg/Dr/Xt | VUS (PM2, PP3) |
| EG37_1 | CDON chr11:125887048 T>C | NM_016952: c.863A>G: p.(Tyr288Cys) | Homozygous; biparental | 1/251320 No HZ | Prob. D; 1.0 | DC; 0.999 | 25.9 | Pt/Mm/Fc/Mmus/Dr/Dm | VUS (PP3, PP4) |
| EG21_1 | IQGAP1 chr15:91017314A>C | NM_0038704: c.2524A>C: p.(Ile842Leu) | Homozygous; biparental | 3/250952 No HZ | Poss. Dr; 0.924 | DC; 0.999 | 25.4 | Pt/Mm/Fc/Mmus/Gg/Tr/Dr/Ce/Xt | VUS (PP3) |
| EG42_1 | WDR37 chr10:1118109G>A | NM_014023.3: c.14G>A: p.(Ser5Asn) | Homozygous; biparental | 2/251418 No HZ | Benign; 0.004 | DC; 0.999 | 23.4 | Pt/Mm/Fc/Mmus/Gg/Dr/Xt | VUS (PP3) |
| EG17_1 | CASK chr23:41446185C>T | NM_001126054: c.1289G>A: p.(Arg430His) | Hemizygous; maternal | 47/203108 No HZ | – | DC; 0.999 | 23.4 | Pt/Mm/Fc/Mmus/Gg/Tr/Dr/Dm/Xt | VUS (PP3) |
| EG14_1 | COL4A1 chr13:110835413C>A | NM_001845.4: c.2022G>T: p.(Arg674Ser) | Hemizygous; Maternal | 2/246948 No HZ | Prob. D; 0.990 | DC; 0.999 | 22.6 | Pt/Mm/Fc/Mmus/Gg/Xt | VUS (PP3) |
| EG14_1 | FAT1 chr4:187540896C>A | NM_005245.4: c.6844G>A: p.(Val2282Met) | Heterozygous; paternal | Absent | Benign; 0.245 | DC; 0.999 | 22.3 | Pt/Mm/Mmus/Gg/Tr/Dr/Xt | VUS (PM2) |
| EG29_1 | MYO10 chr5:16681534 T>C | NM_012334.3: c.4268A>G: p.(His1423Arg) | Heterozygous; paternal | Absent | Benign; 0.044 | DC; 1.0 | 21.2 | Pt/Mm/Mmus/Gg/Tr/Dr/Xt | VUS (PM2) |
| EG42_1 | POMT1 chr9:134396833G>A | NM_007171.3: c.1865G>A: p.(Arg622Gln) | Hemizygous; maternal | 9/282808 No HZ | Poss D; 0.612 | DC; 0.999 | 21.1 | Pt/Mm/Mmus/Gg/Tr/Dr/Xt | VUS (PP3) |
| EG42_1 | POMT1 chr9:134385176G>T | NM_007171.3:c.586G>T: p.(Ala196Ser) | Hemizygous; paternal | Absent | Benign; 0.094 | PMs; 0.999 | 20.2 | Pt/Mm/Gg | VUS (PM2) |
| EG46_1 | GDF6 chr8:97157179G>T | NM_001001557.2: c.980C>A: p.(Pro327His) | Heterozygous; paternal | 77/149532 No HZ | Benign; 1.0 | DC: 0.057 | 16.8 | Pt/Mm/Fc/Mmus | VUS (PP5) |
| EG28_1 | KDM6A chr23:44941845_ 44941847delCAT | ENST00000382899.4 c.3190_3192delCAT: p.(His1064del) | Hemizygous; maternal | – | – | DC; 0.999 | – | Pt/Mm/Fc/Mmus/Gg | VUS (PM4; PM2) |
a
Genes are ordered from highest to lowest CADD scores in each category.
b
DC, disease-causing.
c
P, pathogenic; abbreviations from reference 6.
d
Prob. D, probably damaging.
e
Pt, Pan troglodytes.
f
Mmus, Mus musculus.
g
Dr, Danio rerio.
h
Dm, Drosophila melanogaster.
i
Ce, Caenorhabditis elegans.
j
Xt, Xenopus tropicalis.
k
LP, likely pathogenic.
l
HZ, homozygous.
m
Mm, Macaca mulatta.
n
Fc, Felis catus.
o
VUS, variant of unknown significance.
p
Gg, Gallus gallus.
q
Tr, Takifugu rubripes.
r
Poss. D, possibly damaging.
s
PM, polymorphism.