Table 1.
Presumed Pathogenic WFS1 Variants Identified in This Study and Analysis of the Variants by Predictive Programs
| Polyphen2 | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Nucleotide Change NM_006005 | Protein Effect | Variant Type | Allele Numbers | HumDiv | HumVar | Mutation Taster | SIFT | 1000G ALL/EAS | gnomeAD ALL/EAS | Source | ACMG | |
| Intron 1 | c.-6+6T>C | p.(?) | SP | 1 | — | — | — | — | — | — | Novel | LP* |
| Exon 4 | c.453_460+6delins20bp‡ | p.(Asp151Glufs*3) | FS | 1 | — | — | DC | — | — | — | Novel | P |
| Exon 5 | c.505G>A | p.(Glu169Lys) | MS | 1 | PD | PD | DC | T | — | 0.00002/0.00005 | 2 | P |
| Intron 6 | c.712+681C>T | p.Gly238Lysfs*27 | DI | 1 | — | — | — | — | — | — | Novel | LP† |
| Exon 8 | c.1037C>T | p.(Pro346Leu) | MS | 1 | PD | PD | DC | D | — | 0.00002/0.0001 | 28 | P |
| Exon 8 | c.1097_1107dup | p.(Ala370Argfs*76) | FS | 3 | — | — | DC | — | — | — | 29 | P |
| Exon 8 | c.1174C>T | p.(Gln392*) | NS | 1 | — | — | DC | — | — | — | 30 | P |
| Exon 8 | c.1235T>C | p.(Val412Ala) | MS | 1 | PD | PD | DC | D | 0.001/0.007 | 0.001/0.009 | 15 | P |
| Exon 8 | c.1283C>A | p.(Pro428His) | MS | 1 | PD | PD | DC | D | — | — | Novel | LP |
| Exon 8 | c.1285T>C | p.(Cys429Arg) | MS | 1 | PD | PD | DC | T | — | 0.000008/0.0001 | Novel | LP |
| Exon 8 | c.1300_1302del | p.(Val434del) | IF | 1 | — | — | P* | — | — | — | 31 | P |
| Exon 8 | c.1403dup | p.(Ser469Ilefs*74) | FS | 1 | — | — | DC | — | — | — | Novel | P |
| Exon 8 | c.1424C>T | p.(Pro475Leu) | MS | 1 | PD | B | DC | T | - | 0.000016/0 | Novel | LP |
| Exon 8 | c.1523_1524del | p.(Tyr508Cysfs*34) | FS | 1 | — | — | DC | — | — | — | 32 | P |
| Exon 8 | c.1525_1539del | p.(Val509_Tyr513del) | IF | 1 | — | — | P* | — | — | — | 6 | P |
| Exon 8 | c.1553T>C | p.(Met518Thr) | MS | 1 | PD | PD | DC | D | — | — | Novel | LP |
| Exon 8 | c.1600T>G | p.(Tyr534Asp) | MS | 2 | PD | PD | DC | T | — | — | Novel | LP |
| Exon 8 | c.1618T>G | p.(Trp540Gly) | MS | 1 | PD | PD | DC | D | — | — | Novel | LP |
| Exon 8 | C.1672C>T | p.(Arg558Cys) | MS | 1 | PD | PD | DC | D | — | 0.001/0 | 13 | P |
| Exon 8 | c.1673G>A | p.(Arg558His) | MS | 1 | PD | PD | DC | D | — | 0.000068/0.000109 | 2 | P |
| Exon 8 | c.1885C>T | p.(Arg629Trp) | MS | 1 | PD | PD | P* | T | 0.0002/0 | 0.00001/0 | 2 | P |
| Exon 8 | c.1956C>G | p.(Tyr652*) | NS | 1 | — | — | DC | — | — | — | Novel | LP |
| Exon 8 | c.1997G>A | p.(Trp666*) | NS | 1 | — | — | DC | — | — | — | 31 | P |
| Exon 8 | c.2006A>G | p.(Tyr669Cys) | MS | 1 | PD | PD | DC | D | — | — | 32 | P |
| Exon 8 | c.2020G>A | p.(Gly674Arg) | MS | 4 | PD | PD | DC | D | 0.0002 | 0.0002/0.0002 | 2 | P |
| Exon 8 | c.2070_2079del | p.(Cys690Trpfs*17) | FS | 1 | — | — | DC | — | — | — | Novel | P |
| Exon 8 | c.2100G>T | p.(Trp700Cys) | MS | 1 | PD | PD | DC | D | – | – | 12 | P |
| Exon 8 | c.2146G>A | p.(Ala716Thr) | MS | 1 | PD | PD | DC | T | — | 0.000004/0 | 15 | P |
| Exon 8 | c.2168T>C | p.(Leu723Pro) | MS | 2 | PD | PD | DC | D | — | — | 13 | P |
| Exon 8 | c.2171C>G | p.(Pro724Arg) | MS | 1 | PD | PD | DC | D | — | — | Novel | LP |
| Exon 8 | c.2217C>A | p.(Tyr739*) | NS | 1 | — | — | DC | — | — | — | Novel | P |
| Exon 8 | c.2425G>T | p.(Glu809*) | NS | 2 | — | — | DC | — | — | — | 33 | P |
| Exon 8 | c.2534T>G | p.(Ile845Ser) | MS | 1 | PD | PD | DC | T | — | 0.00002/0.00027 | Novel | LP |
| Exon 8 | c.2576G>C | p.(Arg859Pro) | MS | 1 | PD | PD | DC | D | — | — | 15 | P |
| Exon 8 | c.2643_2646del | p.(Phe882Serfs*69) | FS | 1 | — | — | DC | — | — | — | 34 | P |
| Exon 8 | c.2643_2644del | p.(Phe883Leufs*56) | FS | 1 | — | — | DC | — | — | — | Novel | P |
| Exon 8 | c.928_1183dup | p.(Val395Glyfs*232) | CNV | 1 | — | — | — | — | — | — | Novel | P |
| Exon 8 | g.6237437-6307683del | p.(?) | CNV | 2 | – | – | – | – | – | – | Novel | P |
B, benign; CNV, copy number variant; D, damaging; DC, disease causing; EAS, east Asian; FS, frameshift; IF, in-frame; LP, likely pathogenicity; MS, missense; NS, nonsense; SP, splicing; P, pathogenicity; P*, polymorphism; PD, probably or possibly damaging; T, tolerated.
*
NetUTR predicted to induce aberrant splicing.
†
Five algorithms (Human Splicing Finder, Alternative Splice Site Predictor, MaxEntScan, NetGene2, and NNSplice) predicted to induce aberrant splicing.
‡
Full sequence: GGCTTAGAACAGCCTCTAAG.