Table 6 List of 24 SAFD variants annotated for clinical significance in ClinVar and OMIM.
Chr: Position; dbSNP_ID_Ref_Alt; Gene | KUWAITI | 1KGP | gnomAD | Inheritance mode | Disease name; PMIM; number of OMIM listed genes; Is the disorder seen in Arab population?@ | |||
|---|---|---|---|---|---|---|---|---|
KWT_MAF | Max_Pop (MAF) | 1KGP_MAF | Max_Pop (MAF) | gnomAD_MAF | Max_Pop (MAF) | |||
A. 2 “Pathogenic” variants as per ClinVar annotation | ||||||||
8:143994266; rs61757294_ A_G c.1157T > C; p.Val386Ala CYP11B2 | 0.1519 This has DR mode of inheritance – both this and another variant rs289316 need to be homozygous; hence this higher MAF is alright though the variant is “pathogenic”. | KWS (0.1698) | 0.0531 | EUR (0.1093) | 0.0846 | ASJ (0.1163) | DR (both rs61757294 and rs28931609 need to be homozygous) | Corticosterone methyloxidase type 2 deficiency. PMIM: 610600; Single gene. Rare Genetic disorder. Yes, disorder seen in Arab country. |
10:101829514 rs61751507_ C_T c.533G>A; p.Gly178Asp CPN1 | 0.0747 (high MAF for “pathogenic” variant). ClinVar annotates this variant as pathogenic based on one literature publication which reports this variant in just one patient. Thus, it is possible that the significance is of insufficient evidence and that the variant may become “likely benign”. | KWS (0.0981) | 0.0266 | AMR (0.0634) | 0.0423 | AMR (0.0668) | AR | Carboxypeptidase N deficiency PMIM: 212070 Single gene. Familial Carboxypeptidase N deficiency is a rare disorder. |
B. 4 Drug response variants as per ClinVar annotation | ||||||||
16:31105945 rs61742245_ C_A c.106G>T; p.Asp36Tyr VKORC1 | 0.0104 | KWB (0.0294) | 0.0004 | EUR (0.0010) | 0.0024 | ASJ (0.0384) | AD | Warfarin resistance PMIM: 122700 Multiple genes and rare disorder. Appears already in Table 3 as drug response. |
8:18257854 rs1801280_ T_C c.208G>A; p.Asp70Asn NAT2 | 0.3927 | KWP (0.3879) | 0.2927 | EUR (0.4493) | 0.3821 | FIN (0.4668) | AR Forms part of NAT2*5B haplotype | Slow acetylator due to N-acetyltransferase enzyme variant. Toxicity to the drugs of cisplatin or cyclophosphamide. PMIM: 243400 Yes, disorder seen in Arab country. |
10:96702047 rs1799853_ C_T c.430C>T; p.Arg144Cys CYP2C9 | 0.1181 | KWS (0.1262) | 0.0479 | EUR (0.1243) | 0.0926 | ASJ (0.1357) | AD | Warfarin sensitivity PMIM: 122700 Multiple genes. |
19:15990431 rs2108622_ C_T c.1297G>A; p.Val433Met CYP4F2 | 0.4102 | KWS (0.4541) | 0.2368 | SAS (0.4131) | 0.2735 | SAS (0.3978) | Na | Acenocoumarin response – Dosage. Warfarin sensitivity. PMIM: 122700 Multiple genes. |
C. 14 Risk factor variants | ||||||||
C. 1. 7 Risk factor variants as per ClinVar annotation for complex disorders | ||||||||
2:138759649 rs11558538_ C_T c.314C>T; p.Thr105Ile HNMT | 0.1259 | KWS (0.1495) | 0.0595 | SAS (0.1053) | 0.1008 | FIN (0.1601) | AD | Asthma, susceptibility to; PMIM: 600807 Multiple genes. Yes, disorder seen in Arab country. |
4:100268190 rs283413_ C_A# $ c.232G>T; p.Gly78Arg ADH1C | 0.0653 | KWP (0.1071) | 0.0072 | SAS (0.0174) | 0.0157 | ASJ (0.0633) | IC,Mu | Parkinson’s disease, susceptibility to; PMIM: 168600 Multiple genes. |
5:95751785 rs6232_ T_C c.661A>G; p.Asn221Asp PCSK1 | 0.0594 | KWB (0.0909) | 0.0210 | SAS (0.0501) | 0.0390 | SAS (0.0659) | ? | Obesity, susceptibility to, Body mass index quantitative trait locus 12 PMIM: 612362. OMIM lists single gene but in reality, BMI is associated with multiple genes. |
10:64415184 rs7076156_ G_A# & c.1130-972G>A; p.Ala62Pro ZNF365 | 0.3351 | KWS (0.4450) | 0.1288 | EUR (0.2734) | 0.2044 | ASJ (0.2795) | Na | Uric acid nephrolithiasis, susceptibility to; PMIM: 605990. OMIM lists single gene but this is a multifactorial disorder. |
14:104165753 rs861539_ G_A c.1849-1239G>A; p.Thr241Met XRCC3 | 0.3864 | KWS (0.4450) | 0.2169 | EUR (0.3936) | 0.2904 | ASJ (0.4015) | AD | Cutaneous malignant melanoma 6, susceptibility to PMIM: 613972. OMIM lists single gene but this is a multifactorial disorder. |
17:5485367 rs12150220_ A_T c.464T>A; p.Leu155His NLRP1 | 0.4377 | KWP (0.4643) | 0.1921 | EUR (0.4443) | 0.3674 | ASJ (0.4744) | AR | Vitiligo-associated multiple autoimmune disease susceptibility 1; PMIM: 606579. OMIM lists single gene but this is a multifactorial disorder. |
17:48437456 rs6504649_ C_G c.2402C>G; p.Thr801Arg XYLT2 | 0.4414 | KWB (0.4706) | 0.2510 | EUR (0.4006) | 0.3312 | ASJ (0.4536) | AR | Pseudoxanthoma elasticum, modifier of severity; PMIM: 264800. OMIM lists multiple genes: XYLT1, XYLT2, ABCC6. Yes, disorder seen in Arab country. |
C. 2. 7 Risk factor variants as per our inference but annotated as “pathogenic” in ClinVar annotation | ||||||||
9:116153891 rs1800435_ C_G c.177G>C; p.Lys59Asn ALAD | 0.1241 | KWB (0.1912) | 0.0635 | SAS (0.1585) | 0.0830 | ASJ (0.2207) | AR | Aminolevulinate dehydratase, ALAD*1/ALAD*2 allele at this position associated with susceptibility to lead poisoning. PMIM: 612740. Lead poisoning is becoming a common disease. Single gene. |
10:54531242 rs5030737_ G_A c.154C>T; p.Arg52Cys MBL2 | 0.0790 | KWP (0.0902) | 0.0272 | EUR (0.0596) | 0.0558 | ASJ (0.1032) | AD | Mannose-binding lectin deficiency. PMIM: 614372 Single gene. Complex trait |
15:100230557 rs121918530_ A_G c.782A>G; p.Asn261Ser MEF2A | 0.0103 | KWB (0.0294) | 0.0004 | EUR (0.0020) | 0.0008 | NFE (0.0015) | AD | Coronary artery disease/myocardial infection PMIM: 608320 Single gene. Complex trait |
17:12899902 rs5030739_ C_T c.1621G>A; p.Ala541Thr ELAC2 | 0.0842 | KWS (0.1055) | 0.0232 | SAS (0.0501) | 0.0349 | ASJ (0.0510) | AR or AD? Has to be seen in compound heterozygous state with another variant rs4792311. | Susceptibility to Prostate cancer, hereditary, 2′ PMIM: 614731 Single gene. Complex trait |
17:12915009 rs4792311_ G_A c.650C>T; p.Ser217Leu ELAC2 | 0.3552 | KWP (0.3611) | 0.2145 | EUR (0.3151) | 0.2742 | ASJ (0.3699) | AR or AD? Has to be seen in compound heterozygous state with the previous variant of rs5030739. | Susceptibility to Prostate cancer, hereditary, 2′; PMIM: 614731 Single gene. Complex trait |
17:79767715 rs1801483_ G_A c.118G>A; p.Gly40Ser GCGR | 0.0378 | KWS (0.0505) | 0.0042 | EUR (0.0149) | 0.0075 | ASJ (0.0120) | AD | Diabetes mellitus type 2, non-insulin dependent; PMIM: 125853; Multiple genes. Multifactorial complex disorder. Yes, disorder seen in Arab country. |
18:55373793 rs34719006_ C_T c.208G>A; p.Asp70Asn ATP8B1 | 0.0258 | KWS (0.0413) | 0.0018 | AFR (0.0045) | 0.0031 | ASJ (0.0096) | AD | Cholestasis of pregnancy; PMIM: 147480 Single gene. However, it is the most common liver disease unique to pregnancy. Complex trait. |
D. 2 variants associated with complex traits by GWAS studies followed by clinical testing as per ClinVar annotation | ||||||||
2:27730940 rs1260326_ C_T# c.1337T>C; p.Leu446Pro GCKR | 0.3945 | KWS (0.4352) | 0.2933 | EAS (0.4812) | 0.3667 | ASJ (0.5344) | Not available | Fasting plasma glucose level quantitative trait locus 5 PMIM: 613463 Single gene (but, FPG levels are associated with multiple genes). |
11:68846399 rs35264875_ A_T c.1450A>T; p.Met484Leu TPCN2 | 0.1832 | KWP (0.2260) | 0.0996 | SAS (0.2055) | 0.1593 | FIN (0.2980) | Not available | Skin/hair/eye pigmentation, variation in, SHEP10 PMIM: 612267; OMIM lists single gene (but, the variations in skin/hair/eye pigmentation variations are associated with multiple genes). |
E. 2 Protective variants as per ClinVar annotation | ||||||||
4:100260789rs698_ T_C c.1048A > G; p.Ile350Val ADH1C This variant is in LD with the variant R271Q (corresponding to the variant listed in the next row rs1693482) that is responsible for the differences in enzymatic differences | 0.3137 | KWS (0.3515) | 0.2143 | EUR (0.4046) | 0.3470 | FIN (0.5169) | Ic, Mu | Alcohol dependence, protection against; PMIM: 103780. Multiple genes. |
4:100263965 rs1693482_ C_T c.815G>A; p.Arg272Gln ADH1C | 0.3296 | KWS (0.3830) | 0.2143 | EUR (0.4046) | 0.3462 | FIN (0.5167) | Ic, Mu | Alcohol dependence, protection against; PMIM: 103780. Multiple genes. |
