Table 2.
Annotations of SNV/InDel variants, including bioinformatic predictions, variant frequency and ACMG classification of variants
| Patient ID | Gene | Variant | ACMG | Variant type | GnomAD PopMax* | GnomAD FIN* | GnomAD NFE* | CADD | GERP + + RS | ADA SCORE | HSF |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Known gene—known variant | |||||||||||
| FIN3 | PPP2R5D | NM_006245.4:c.592G > A:p.(E198K) | P | Missense | – | – | – | 33 | 5.84 | – | – |
| FIN11 | CYFIP2 | NM_001291722.2:c.1993G > A:p.(E665K) | P | Missense | – | – | – | 35 | 5.63 | – | – |
| FIN17 | MED12 | NM_005120.3:c.2881C > T:p.(R961W) | P | Missense | – | – | – | 35 | 5 | – | – |
| FIN24 | ACTB | NM_001101.5:c.1043C > T:p.(S348L) | P | Missense | – | – | – | 30 | 4.66 | – | – |
| FIN37 | DYNC1H1 | NM_001376.5:c.4700G > A:p.(R1567Q) | P | Missense | – | – | – | 34 | 4.88 | – | – |
| FIN38 | CRADD | NM_003805.5:c.509G > A:p.(R170H)** | P | Missense | 0.0049 | 0.0049 | 1.00E-04 | 27 | 4.69 | – | – |
| FIN52 | HUWE1 | NM_031407.7:c.9208C > T:p.(R3070C) | P | Missense | – | – | – | 34 | 5.88 | – | – |
| Known gene—novel variant | |||||||||||
| FIN6 | HNRNPK | NM_031263.4:c.1294delG:p.(D432fs) | P | Frameshift indel | – | – | – | – | – | – | – |
| FIN12 | ARX | NM_139058.3:c.558_560dup:p.(P187dup) | VUS | Nonframeshift indel | – | – | – | – | – | – | – |
| FIN14 | CTBP1 | NM_001328.3:c.158_160del:p.(F53del) | LP | Nonframeshift indel | – | – | – | – | – | – | – |
| FIN20 | CHAMP1 | NM_032436.4:c.1858A > T:p.(K620*) | P | Nonsense | – |
– – |
– | 40 | 5.6 | – | – |
| FIN33 | RAI1 | NM_030665.4:c.3594G > T:p.(R1198S) | LP | Missense | – | – | – | 14.55 | 2.1 | – | – |
| FIN36 | LAMB1 | NM_002291.2:c.5002delG:p.(E1668fs) | LP | Frameshift indel | 4.62E-05 | 4.62E-05 | 0 | – | – | – | – |
| FIN36 | LAMB1 | NM_002291.2:c.2315-28A > G | VUS | Splicing (3′ branch point) | 0.0024 | 0.0024 | 1.86E-05 | 2.793 | -4.39 | – | Alteration of auxiliary sequences; New Donor splice site; possible branch point area |
| FIN38 | CRADD | NM_003805.5:c.2 T > C:p.(M1?) | P | Start loss | – | – | – | 25.6 | 5.19 | – | – |
| FIN42 | P4HTM | NM_177939.2:c.1238C > T:p.(P413L) | LP | Missense | 0.0006 | 0.0006 | 0 | 34 | 5.53 | – | – |
| FIN49 | SCN1A | NM_001202435.3:c.1891A > G:p.(M631V) | VUS | Missense | – | – | – | 0.853 | 3.88 | – | – |
| FIN53 | TRIO | NM_007118.4:c.3908C > T:p.(T1303I) | LP | Missense | – | – | – | 32 | 6.03 | – | – |
| FIN53 | SON | NM_138927.4:c.6869A > C:p.(Q2290P) | VUS | Missense | – | – | – | 23.4 | 5.85 | – | – |
| FIN-ID4 | KIAA2022 | NM_001008537.3:c.3244C > T:p.(Q1082*) | P | Nonsense | – | – | – | 39 | 5.28 | – | – |
| FIN-ID8 | GRIN2A | NM_001134408.2:c.452_463del:p.(I151_A155delinsT) | LP | Nonframeshift indel | – | – | – | – | – | – | – |
| FIN-ID10 | ANKRD11 | NM_001256183.2:c.6793delG:p.(A2265fs) | P | Frameshift | – | – | – | – | – | – | – |
| Known gene—novel variant—phenotypic expansion | |||||||||||
| FIN5 | SAMD9L | NM_001350084.2:c.2722A > G:p.(I908V) | LP | Missense | – | – | – | 11.85 | 5.22 | – | – |
| FIN8 | BCL11A | NM_022893.4:c.977C > A:p.(T326K) | LP | Missense | – | – | – | 26 | 5.84 | – | – |
| FIN28 | MECP2 | NM_001110792.2:c.1174_1199del:p.(V392fs) | P | Frameshift indel | – | – | – | – | – | – | – |
| FIN35 | MYT1 | NM_004535.3:c.790G > C:p.(E264Q) | LP | Missense | – | – | – | 17.3 | 3.77 | – | – |
| FIN35 | COL9A2^ | NM_001852.4:c.1145G > T:p.(G382V) | LP | Missense | – | – | – | 33 | 5.74 | – | – |
| FIN-AIC3 | ZC3H14 | NM_207661-2:c.1177 + 9 T > C(splice region) | VUS | Splicing | 0.0035 | 0.0035 | 0.0005 | 14.22 | 1.59 | – | 5′ donor; no effect on splicing predicted |
| Alternate inheritance model | |||||||||||
| FIN7 | UBA7 | NM_003335.3:c.1904 + 3A > G (splicing) | NA (VUS) | Splicing | – | – | – | 18.29 | 3.58 | 0.9332 | Broken WT Donor Site |
| FIN46 | DDX47 | NM_016355.4:c.1129C > A:p.(R377S) | NA (VUS) | Missense | – | – | – | 30 | 5.75 | – | – |
| FIN-ID9 | DHX58 | NM_024119.3:c.1910G > A:p.(S637N) | NA (VUS) | Missense | 1.77E-05 | 0 | 1.77E-05 | 11.78 | 3.12 | – | – |
| Candidate variants In potential novel genes | |||||||||||
| FIN4 | NTRK1 | NM_002529.3:c.2271C > G:p.(Y757*) and c.2271C > T:p.(Y757 =) (mixture of both variants) | NA (VUS) | Nonsense | – | – | – | 38 | 0.887 | – | – |
| FIN21 | SYPL1 | NM_006754.4:c.152G > A:p.(C51Y) | NA (VUS) | Missense | 0.0064 | 0.0064 | 0.0007 | 28.8 | 4.97 | – | – |
| FIN23 | ITPR2 | NM_002223.4:c.541A > G:p.(K181E) | NA (VUS) | Missense | – | – | – | 28.7 | 5.02 | – | – |
| FIN27 | ZKSCAN1 | NM_001287054.3:c.1302C > G:p.(F434L) | NA (VUS) | Missense | – | – | – | 27.8 | 4.19 | – | – |
| FIN32 | ZFR | NM_016107.5:c.2667C > G:p.(D889E) | NA (VUS) | Missense | – | – | – | 23.9 | 5.49 | – | – |
| FIN45 | POLR2F | NM_001301130.2:c.294-2A > G (splicing) | NA (VUS) | Splicing | – | – | – | 23.2 | 4.42 | 0.7508 | New cryptic 3′ Acceptor splice site -2 |
| FIN47 | DNAH3 | NM_017539.2:c.11965A > G:p.(I3989V) | NA (VUS) | Missense | – | – | – | 25.8 | 5.55 | – | – |
| FIN-ID3 | ERGIC3 | NM_015966.3:c.717 + 1G > A (splicing) | NA (VUS) | Splicing | 0.0002 | 0.0002 | 0 | 28.2 | 4.62 | 1 | Broken WT Donor Site |
| FIN-AIC2 | KIF1B | NM_183416.4:c.2066C > T:p.(P689L) | NA (VUS) | Missense | 0.0007 | 0.0007 | 2.64E-05 | 19.56 | 6.13 | – | – |
| FIN-AIC2 | KIF1B | NM_015074.3:c.2543C > T:p.(P848L) | NA (VUS) | Missense | – | – | – | 24.4 | 5.74 | – | – |
*Based on gnomADv2.1.1 exomes
**Known pathogenic variant in trans with novel variant NM_003805.5:c.2 T > C:p.(M1?)
^Not a known ID gene but could contribute to the skeletal phenotype seen in this family