Table 1.
Variants identified by next generation sequencing (NGS).
| PT-ID a | Gene Name | cDNA Change | Protein Change | dbSNP ID b | ACMG Classification | Global MAF c | Population MAF d | SIFT Score | Polyphen Score | Mutation Taster Pred | CADD |
|---|---|---|---|---|---|---|---|---|---|---|---|
| ALS literature | |||||||||||
| ALS_78 | ALS2 | c.1115C > G | p.Pro372Arg | rs190369242 | 3 | 0.00130 | 0.00220 | 0.64 (T) | 0.919 (D) | 0.683 (D) | 19.65 |
| ALS_6 | OPTN | c.941A > T | p.Gln314Leu | rs142812715 | 3 | 0.00017 | 0.00030 | 0.01 (D) | 0.999 (D) | 0.993 (D) | 27.70 |
| ALS_56 | SETX | c.654G > C | p.Lys218Asn | rs117861188 | 3 | 0.00033 | 0.00060 | 0.0 (D) | 0.961 (D) | 0.900 (D) | 23.80 |
| ALS_34 | SOD1 | c.203T > C | p.Leu68Pro | CM110553 | 5 | 0.00000 | 0.00000 | 0.21 (T) | 0.001 (B) | 0.99 (N) | 6.15 |
| ALS_6 | SOD1 | c.217G > A | p.Gly73Ser | rs121912455 | 5 | 0.00000 | 0.00000 | 0.0 (D) | 0.970 (D) | 0.999 (D) | 29.30 |
| ALS_23 | TBK1 | c.1190T > C | p.Ile397Thr | rs755069538 | 5 | 0.00010 | 0.00030 | 0.31 (T) | 0.039 (B) | 0.999 (D) | 22.80 |
| ALS and non-ALS literature | |||||||||||
| ALS_5 | SETX | c.59G > A | p.Arg20His | rs79740039 | 3 | 0.00683 | 0.01051 | 0.25 (T) | 0.001 (B) | 0.999 (N) | 3.43 |
| ALS_18 | SETX | c.59G > A | p.Arg20His | ||||||||
| ALS_60 | SETX | c.59G > A | p.Arg20His | ||||||||
| ALS_4 | SPG11 | c.1348A > G | p.Ile450Val | rs3759873 | 1 | 0.01672 | 0.00450 | 0.78 (T) | 0 (B) | 0.994 (D) | 6.31 |
| ALS_30 | SPG11 | c.3037A > G | p.Lys1013Glu | rs111347025 | 2 | 0.00861 | 0.01448 | 0.73 (T) | 0.002 (B) | 0.963 (D) | 22.70 |
| ALS_43 | SPG11 | c.3037A > G | p.Lys1013Glu | ||||||||
| ALS_32 | SPG11 | c.6224A > G | p.Asn2075Ser | rs140824939 | 3 | 0.00310 | 0.00489 | 0.49 (T) | 0 (B) | 0.999 (N) | 0.28 |
| Non-ALS literature | |||||||||||
| ALS_2 | BSCL2 | c.844G > A | p.Ala282Thr(218)§ | rs190842600 | 3 | 0.00022 | 0.00000 | 0.08 (T) | 1 (D) | 0.999 (D) | 25.90 |
| ALS_53 | BSCL2 | c.1033C > T | p.Arg345Trp(281)§ | rs767820877 | 3 | 0.00000 | 0.00000 | 0.02(D) | 0.987 (D) | 0.999 (D) | 21.40 |
| ALS_41 | HSPB3 | c.347G > C | p.Arg116Pro | rs150931007 | 4 | 0.00011 | 0.00010 | 0 (D) | 1 (D) | 0.999 (D) | 29.70 |
| ALS_1 | MFN2 | c.1574A > G | p.Asn525Ser | rs145654854 | 3 | 0.00017 | 0.00021 | 1 (T) | 0 (B) | 0.753 (N) | 19.62 |
| ALS_6 | SETX | c.4612C > T | p.Arg1538Trp | rs147018359 | 3 | 0.00000 | 0.00000 | 0.21 (T) | 0 (B) | 0.999 (N) | 17.31 |
| ALS_29 | SETX | c.4612C > T | p.Arg1538Trp | ||||||||
| ALS_30 | SPG11 | c.5986_5987insT | p.Cys1996Leufs*4 | rs312262775 | 5 | 0.00002 | 0.00000 | - | - | - | - |
| ALS_7 | SQSTM1 | c.352C > T | p.Pro118Ser | rs200152247 | 3 | 0.00006 | 0.00010 | 0.54 (T) | 0.009 (B) | 0.999 (D) | 20.90 |
| ALS_34 | SQSTM1 | c.802C > G | p.Leu268Val | rs753685955 | 3 | 0.00001 | 0.00000 | 1 (T) | 0.004 (B) | 0.824 (N) | 17.73 |
| Variants present only in population databases | |||||||||||
| ALS_64 | BSCL2 | c.689G > A | p.Ser230Asn (166) § | rs778378228 | 4 | 0.00001 | 0.00000 | 0.11 (T) | 0.820 (P) | 0.824 (N) | 23.40 |
| ALS_67 | BSCL2 | c.785C > T | p.Ala262Val(198) § | rs140896339 | 3 | 0.00028 | 0.00000 | 0.50 (T) | 0.085(B) | 0.999 (N) | 18.85 |
| ALS_7 | BSCL2 | c.1057T > A | p.Ser353Thr(189) § | rs769769807 | 3 | 0.00001 | 0.00000 | 0.17 (T) | 0.006 (B) | 0.999 (N) | 6.03 |
| ALS_69 | BSCL2 | c.1282C > T | p.Pro428Ser(364) § | rs369732238 | 3 | 0.00006 | 0.00010 | 0.1 (T) | 0.573 (P) | 0.905 (N) | 18.59 |
| ALS_43 | BSCL2 | c.1300T > C | p.Ser434Pro(370) § | rs199584887 | 3 | 0.00006 | 0.00000 | 0.44 (T) | 0.001 (B) | 0.999 (N) | 1.58 |
| ALS_52 | DCTN1 | c.1486G > C | p.Val496Leu | rs773897036 | 4 | 0.00002 | 0.00000 | 0.06 (T) | 0.984 (D) | 0.999 (D) | 23.50 |
| ALS_13 | DYNC1H1 | c.265G > A | p.Gly89Ser | rs749973847 | 3 | 0.00002 | 0.00000 | 0.74 (T) | 0.019 (B) | 0.999 (D) | 22.80 |
| ALS_40 | DYNC1H1 | c.3748G > A | p.Val1250Met | rs369914512 | 3 | 0.00006 | 0.00010 | 0.07 (T) | 0.978 (D) | 0.999 (D) | 29.20 |
| ALS_41 | DYNC1H1 | c.12213C > T # | p.Ile4071Ile | rs746950373 | 3 | 0.00002 | 0.00000 | 0.48 (T) | - | 1 (D) | 12.50 |
| ALS_33 | HSPB1 | c.403T > G | p.Ser135Ala | rs766728475 | 4 | 0.00002 | 0.00000 | 0.07 (T) | 0.623 (P) | 0.999 (D) | 25.40 |
| ALS_53 | HSPB3 | c.199G > A | p.Gly67Ser | rs35258119 | 3 | 0.00727 | 0.00000 | 0.2 (T) | 0.036 (B) | 0.999 (N) | 17.28 |
| ALS_4 | HSPB3 | c.346C > T | p.Arg116X | rs757339596 | 4 | 0.00003 | 0.00000 | - | - | 0.999 (D) | 11.58 |
| ALS_58 | PLEKHG5 | c.3049G > A | p.Gly1017Arg | rs755699992 | 3 | 0.00000 | 0.00000 | 0.56 (T) | 0.047 (B) | 0.999 (N) | 0.16 |
| ALS_15 | SETX | c.3182C > T | p.Pro1061Leu | rs12352982 | 3 | 0.01604 | 0.00000 | 1 (T) | 0 (B) | 0.999 (N) | 0.90 |
| ALS_46 | SETX | c.7435A > G | p.Ile2479Val | rs536912256 | 3 | 0.00006 | 0.00000 | 0.43 (T) | 0.001 (B) | 0.999 (N) | 0.76 |
| ALS_73 | SPG11 | c.1675T > A | p.Ser559Thr | rs773680273 | 3 | 0.00001 | 0.00000 | 0.2 (T) | 0.990 (D) | 0.591 (D) | 20.80 |
| ALS_27 | SPG11 | c.2764G > A | p.Val922Ile | rs139399250 | 3 | 0,00006 | 0,00010 | 0.43 (T) | 0.002(B) | 0.999 (N) | 2.25 |
| ALS_67 | SPG11 | c.6201A > T # | p.Gly2067Gly | rs764991726 | 3 | 0,00001 | 0,00000 | 1 (T) | - | 0.987 (D) | 7.48 |
| Novel candidate ALS-associated variants | |||||||||||
| ALS_34 | DYNC1H1 | c.4183A > C | p.Lys1395Gln | - | 4 | - | - | 0.12 (T) | 1.000 (D) | 0.999 (D) | 34.00 |
| ALS_22 | DYNC1H1 | c.5303G > T | p.Ser1768Ile | - | 3 | - | - | 0.1 (T) | 0.028 (B) | 0.999 (N) | 15.71 |
| ALS_27 | FIG4 | c.1030C > A | p.Pro344Thr | - | 4 | - | - | 0.37 (T) | 0.875 (P) | 0.999 (D) | 25.40 |
| ALS_21 | FUS | c.1168 + 7A > G # | - | - | 3 | - | - | - | - | - | - |
| ALS_40 | SETX | c.5852A > T | p.His1951Leu | - | 4 | - | - | 0.13 (T) | 0.961 (D) | 0.974 (D) | 25.80 |
| ALS_70 | SPG11 | c.4826delT | p.Met1609Serfs*31 | - | 4 | - | - | - | - | 1 (D) | 8.99 |
a PT-ID, patient identification code; b dbSNP150; c Global MAF, global allele counts were calculated from all subjects in the ExAc database; d MAF population, population allele count refers to European Ancestry subjects from the ExAc database; §, the variants present in BSCL2 gene has been reported the positions in both isoform NM_001122955.3 and NM_001130702.2 in bracket; #, variants predicted as splice site by in silico tools; ACMG, American College of Medical Genetics and Genomics; ACMG classification: 1 = benign, 2 = likely benign, 3 = uncertain significance, 4 = likely pathogenic, 5 = pathogenic; MAF, minor allele frequency; SIFT: T = tolerated and D = deleterious; Polyphen: B = benign, P = possibly damaging, D = damaging; Mutation Taster: D = disease causing, N = polymorphism, A = disease causing automatic; CADD, combined annotation dependent depletion; CADD scores, scaled CADD scores (Phred like) for scoring deleteriousness. Variants in common between ALS patients and controls were excluded (Table S4).