Table 4 Missense and splice variants of unknown significance detected by NGS-based sequencing
Gene (transcript GRCh37/hg19) | Index patient identifier | Variant type | Exons/total no. of exons | cDNA change | Predicted amino acid change | dbSNP | Total allele frequency, gnomAD; population with highest AFa | In silico predictionb | Splicing predictions at nearest natural junction |
|---|---|---|---|---|---|---|---|---|---|
ALK (NM_004304.4) | 52 | Splice region and synonymous | 17/29 | c.2817C>T | p.(Gly939Gly) | rs112022466 | 0.0001840; SA: 0.0006173 |  | Native acceptor site: MaxEnt: + 23.7% NNSPLICE: + 9.5% HSF: + 0.9% GeneSplicer: + 32.0% |
APC (NM_001127510.2) | 83 | Missense | 17/17 | c.4918C>T | p.(Arg1640Trp) | rs373440614 | 0.00007223; | C | Â |
O: 0.0001548 | Â | ||||||||
ATM (NM_000051.3) | 20 | Missense | 10/63 | c.1271C>A | p.(Pro424His) | rs147472613 | 0.00002188; | D | Â |
A: 0.00004189 | |||||||||
ATM (NM_000051.3) | 20 | Missense | 50/63 | c.7357C>T | p.(Arg2453Cys) | rs755418571 | 0.00001219; | C | Â |
EA: 0.00005807 | |||||||||
BRCA2 (NM_000059.3) | 36 | Missense | 10/27 | c.831T>G | p.(Asn277Lys) | rs28897705 | 0.00006632; | B | Â |
NFE: 0.0001440 | |||||||||
BRCA2 (NM_000059.3) | 30 | Missense | 11/27 | c.6101G>A | p.(Arg2034His) | rs80358849 | 0.000004069; | B | Â |
NFE: 0.000008973 | |||||||||
BRCA2 (NM_000059.3) | 80 | Missense | 14/27 | c.7021C>T | p.(Arg2341Cys) | rs41293505 | 0.00002439; | D | Â |
EA: 0.00005798 | |||||||||
BRIP1 (NM_032043.2) | 68 | Missense | 15/20 | c.2220G>T | p.(Gln740His) | rs45589637 | 0.0005198; | B | Â |
L: 0.001395 | |||||||||
CHEK2 (NM_007194.3 | 79 | Missense | 4/15 | c.539G>A | p.(Arg180His) | rs137853009 | 0.00006494; | C | Â |
L: 0.0002615 | |||||||||
CHEK2 (NM_007194.3) | 83 | Missense | 6/15 | c.688G>C | p.(Ala230Pro) | rs748636216 | 0.000004063; | D | Â |
NFE: 0.000008956 | |||||||||
DDB2 (NM_000107.2) | 23 | Missense | 7/10 | c.947C>T | p.(Ser316Phe) | rs375788966 | 0.00001218; | C | Â |
SA: 0.00003249 | |||||||||
DICER1 (NM_030621.4) | 8 | Missense | 25/29 | c.4228A>T | p.(Asn1410Tyr) | Â | not found | D | Â |
DIS3L2 (NM_152383.4) | 65 | Missense | 20/21 | c.2450C>T | p.(Thr817Met) | rs376816858 | 0.00006697; | C | Â |
SA: 0.0003505 | |||||||||
EGFR (NM_005228.3) | 54 | Missense | 17/28 | c.2039G>A | p.(Arg680Gln) | rs373336251 | 0.00009084; | D | Â |
FE: 0.0003912 | |||||||||
ERCC2 (NM_000400.3) | 24 | Disruptive inframe deletion | 20/23 | c.1857_1859delCAT | p.(Ile619del) | Â | 0.000008127; | Â | Â |
EA: 0.00005800 | |||||||||
ERCC2 (NM_000400.3) | 55 | Missense | 22/23 | c.2083C>T | p.(Arg695Cys) | rs201392911 | 0.0001372; | D | Â |
A: 0.0003331 | |||||||||
ERCC4 (NM_005236.2) | 23 | Missense | 11/11 | c.2395C>T | p.(Arg799Trp) | rs121913049 | 0.0004476; | D | Â |
NFE: 0.0008138 | |||||||||
ERCC5 (NM_000123.3) | 23 | Missense | 1/15 | c.56C>T | p.(Pro19Leu) | rs34291397 | 0.0005702; | C | Â |
NFE: 0.001092 | |||||||||
ERCC5 (NM_000123.3) | 76 | Missense | 13/15 | c.2818G>A | p.(Val940Met) | rs146344855 | 0.0009378; | C | Â |
AJ: 0.005122 | |||||||||
EXT2 (NM_000401.3) | 13 | Missense | 6/14 | c.1064G>A | p.(Arg355His) | rs149727518 | 0.0006422; | D | Â |
AJ: 0.003448 | |||||||||
EXT2 (NM_000401.3) | 54 | Missense | 7/14 | c.1186G>A | p.(Val396Met) | rs138943091 | 0.0004148; | D | Â |
NFE: 0.0007261 | |||||||||
FANCA (NM_000135.2) | 41, 73 | Missense | 1/43 | c.64T>G | p.(Trp22Gly) | Â | not found | D | Â |
FANCA (NM_000135.2) | 8 | Missense | 16/43 | c.1489C>G | p.(Pro497Ala) | Â | not found | D | Â |
FANCA (NM_000135.2) | 27 | Missense | 22/43 | c.2000C > G | p.(Pro667Arg) | rs755293596 | 0.00002230; | D |  |
SA: 0.00004382 | |||||||||
FANCA (NM_000135.2) | 49 | Missense | 35/43 | c.3430C>T | p.(Arg1144Trp) | rs143671872 | 0.0005269; | D | Â |
NFE: 0.0009237 | Â | Â | |||||||
FANCA (NM_000135.2) | 54 | Missense | 37/43 | c.3688C>G | p.(Leu1230Val) | rs576401459 | 0.00002030; | D | Â |
A: 0.00006535 | |||||||||
FANCD2 (NM_033084.3) | 57 | Missense | 21/43 | c.1933G>T | p.(Asp645Tyr) | rs146496253 | 0.0001371; | C | Â |
NFE: 0.0002288 | |||||||||
FANCI (NM_001113378.1) | 35 | Missense | 17/38 | c.1589T>C | p.(Leu530Pro) | rs766346156 | 0.000008122; | D | Â |
SA: 0.00006497 | |||||||||
GPC3 (NM_001164617.1) | 19 | Missense | 8/9 | c.1630C>T | p.(Arg544Cys) | rs759543703 | 0.00009270; | D | Â |
A: 0.0001707 | |||||||||
HNF1A (NM_000545.6) | 48 | Missense | 5/10 | c.1061C>T | p.(Thr354Met) | rs757068809 | 0.00006495; | D | Â |
L: 0.0001743 | |||||||||
KIT (NM_000222.2) | 39 | Missense | 3/21 | c.391G>A | p.(Asp131Asn) | Â | 0.00001807; | C | Â |
A: 0.00004164 | |||||||||
MET (NM_001127500.1) | 13 | Missense | 2/21 | c.1076G>A | p.(Arg359Gln) | rs201274041 | 0.0002347; | D | Â |
NFE: 0.0004298 | |||||||||
MET (NM_001127500.1) | 75 | Missense | 14/21 | c.3023G>A | p.(Ser1008Asn) | Â | not found | D | Â |
MLH1 (NM_000249.3) | 51 | Missense | 13/19 | c.1457C>T | p.(Ser486Phe) | rs532873141 | 0.000004061; | C | Â |
EA: 0.00005798 | |||||||||
NF1 (NM_001042492) | 28 | Missense | 5/58 | c.575G>A | p.(Arg192Gln) | rs587781670 | 0.00005294; | C | Â |
EA: 0.0005803 | |||||||||
NSD1 (NM_022455.4) | 10 | Missense | 23/23 | c.7352G>A | p.(Arg2451Lys) | rs200115665 | 0.0001119; | D | Â |
NFE: 0.0002212 | |||||||||
PALB2 (NM_024675.3) | 56 | Missense | 8/13 | c.2792T>G | p.(Leu931Arg) | rs773831304 | 0.00001221; | D | Â |
NFE: 0.00002694 | |||||||||
PMS1 (NM_000534.4) | 67 | Missense | 2/13 | c.118G>C | p.(Val40Leu) | Â | not found | B | Â |
PMS1 (NM_000534.4) | 12 | Missense | 3/13 | c.287C>A | p.(Ala96Asp) | rs139414606 | 0.000004063; | D | Â |
NFE: 0.000008962 | |||||||||
PTCH1 (NM_001083602.1) | 4 | Missense | 23/24 | c.3749A>G | p.(Tyr1250Cys) | rs147067171 | 0.0005463; | D | Â |
AJ: 0.001098 | |||||||||
RAD51C (NM_058216.2) | 42 | Splice region | 8/8 | c.1026+5_1026+7 delGTA |  | rs747311993 | 0.00001219; |  | Native donor site: SSF: − 100.0% MaxEnt: − 100.0% NNSPLICE: − 99.6% HSF: − 14.8% |
NFE: 0.00002687 | |||||||||
RAD51D (NM_002878.3) | 52 | Missense | 5/10 | c.355T>C | p.(Cys119Arg) | rs201313861 | 0.00005413; | B | Â |
L: 0.00008716 | |||||||||
RHBDF2 (NM_024599.5) | 3, 75 | Missense | 8/19 | c.940G>A | p.(Ala314Thr) | rs140433374 | 0.0007812; | C | Â |
FE: 0.001173 | |||||||||
SDHB (NM_003000.2) | 81 | Missense | 2/8 | c.178A>G | p.(Thr60Ala) | rs34599281 | 0.00006095; | D | Â |
NFE: 0.0001165 | |||||||||
SLX4 (NM_032444.2) | 14 | Missense | 14/15 | c.4831G>A | p.(Glu1611Lys) | rs766110479 | 0.00002847; | D | Â |
EA: 0.00005798 | |||||||||
TSC1 (NM_000368.4) | 51 | Missense | 12/23 | c.1178C>T | p.(Thr393Ile) | rs201452238 | 0.00002170; | D | Â |
A: 0.00004165 | |||||||||
TSC2 (NM_000548.4) | 32 | Missense | 36/42 | c.4582G>C | p.(Glu1528Gln) | Â | not found | D | Â |
WRN (NM_000553.4) | 55 | Missense | 19/35 | c.2131C>T | p.(Arg711Trp) | rs34560788 | 0.0002057; | D | Â |
NFE: 0.0003948 |