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. 2023 May 19;13:8120. doi: 10.1038/s41598-023-33391-w

Table 3.

Non-synonymous variants identified in the five gene candidates associated with a cholestatic phenotype in the Genes and Health cohort.

Gene Phenotype Transcript Protein change dbSNP gnomAD AF G&H AF^ ACMG-AMP ACMG-AMP criteria Clinvar Ref
ABCB4 Intrahepatic cholestasis of pregnancy ENSP00000496956.1:p.Gly1254Ser G1254S* rs781315185 0.00003656 0.00028843 LP PM1, PM2, PP2, PP3 22
ENSP00000497931.1:p.Asp1284Asn P1050S* 0.00019146 LP PM1, PM2, PP2, PP3
ENSP00000496956.1:p.Ala833Thr A833T* 0.00009638 LP PM1, PM2, PP2, PP3
ENSP00000496956.1:p.Asn510Ser N510S rs375315619 0.00019110 0.00057394 LP PM1, PM2, PP2, PP3, PP5 LP 23–30
ENSP00000496956.1:p.Thr175Ala T175A1 rs58238559 0.01155000 0.01315030 LB PM1, PP2, PP3, BS1, BS2, BP6 Benign/likely benign 3,12,23,25,26,28–43
Gallstone disease ENSP00000496956.1:p.Arg1137Gln R1137Q rs780738927 0.00003250 0.00028846 LP PM1, PM2, PP2, PP3
ENSP00000496956.1:p.Gly826Arg G826R* 0.00028681 LP PM1, PM2, PP2, PP3
ENSP00000496956.1:p.Arg788Leu R788L rs8187801 0.00000813 0.00009579 LP PM1, PM2, PP2, PP3 Benign
ENSP00000496956.1:p.Asp686Asn D686N rs78653500 0.00009586 VUS PM2, PP2, BP4
ENSP00000496956.1:p.Met676Ile M676I rs376702091 0.00002033 0.00038278 VUS PM2, PP2, BP4
ENSP00000496956.1:p.Thr651Asn T651N rs45476795 0.0005776 0.0006719 LB PM2, PP2, BP4, BP6 conflicting
ENSP00000496956.1:p.Lys391Glu K391E rs781347049 0.00002440 0.00009582 LB PM2, PP2, BP4, BP6
Cholangiocarcinoma ENSP00000496956.1:p.Gln668His Q668H* 0.00009586 LB PM2, PP2, BP4
ABCB11 Intrahepatic cholestasis of pregnancy ENSP00000497931.1:p.Asp1284Asn D1284N rs766784155 0.00001228 0.00028780 LP PM1, PM2, PP2, PP3
ENSP00000497931.1:p.Arg1050His R1050H rs72549398 0.00000421 0.00019135 VUS PM2, PP2, BP4
ENSP00000497931.1:p.Met677Val M677V2 rs11568364 0.02364000 0.01005750 Benign PP2, BA1, BS3, BP6, BP4 Benign 12,43–52
ENSP00000497931.1:p.Asn591Ser N591S3 rs11568367 0.01436000 0.12647200 Benign PM1, PP2, BA1, BP6 Benign 3,12,28,36,46,52–61
ENSP00000497931.1:p.Val284Ala V284A rs200739891 0.00026040 0.00009558 LP PM1, PM2, PM5, PP2, PP3, BP6 Conflicting 31,48,50
Gallstone disease ENSP00000497931.1:p.Ala1260Pro A1260P rs772097949 0.00001641 0.00028153 LP PM1, PM2, PP2, PP3 VUS
ENSP00000497931.1:p.Gln976Arg Q976R rs199940188 0.00054840 0.00066883 VUS PM1, PM2, PP2, BP4 Conflicting
ENSP00000497931.1:p.Ala926Ser A926S* 0.00040667 LP PM1, PM2, PM5, PP2,PP3
ENSP00000497931.1:p.Ala679Val A679V rs200912109 0.00045560 0.00143761 VUS PM2, PP2, BP4 Conflicting
ENSP00000497931.1:p.Asn539Asp N539D* 0.00022604 VUS PM1, PM2, PP2, BP4
ENSP00000497931.1:p.Arg487Cys R487C rs770693935 0.00002043 0.00009549 LP PM1, PM2, PP2, PP3 62
ENSP00000497931.1:p.Ala311Thr A311T rs200509511 0.00004073 0.00028969 LP PM1, PM2, PP2, PP3
ENSP00000497931.1:p.Val95Ile V95I rs201735739 0.00009766 0.00028708 Benign PM1, PM2, PP2, BP4
ENSP00000497931.1:p.Asp94Asn D94N rs760920706 0.00010170 0.00095621 LP PM1, PM2, PP2 Conflicting
ENSP00000497931.1:p.Lys12Arg K12R* 0.00010378 LP PM1, PM2, PP2, PP3
ATP8B1 Intrahepatic cholestasis of pregnancy ENSP00000497896.1:p.Arg384His R384H# rs2271260 0.00026400 0.00048040 VUS PM2, PP2, BP6 3
Gallstone disease
Gallstone disease ENSP00000497896.1:p.Val1161Ala V1161A rs1255793857 0.00000406 0.00009549 VUS PM2, PP2
ENSP00000497896.1:p.Thr1092Ile T1092I rs780425796 0.00001220 0.00030581 VUS PM2, PP2, PP3
ENSP00000497896.1:p.Met674Thr M674T+4 rs35470719 0.00456300 0.00632063 Benign PP2, BA1, BP4, BP6 Benign/Likely benign 52,63–68
ENSP00000497896.1:p.Ile577Val I577V+5 rs3745078 0.00467800 0.00628992 Benign PP2, BA1, BP6 Benign 52,63–66,68
ENSP00000497896.1:p.His78Gln H78Q+6 rs3745079 0.00421800 0.00495751 Benign PP2, BP4,BP6, BS1, BS2 Benign 52,63–66,68
ENSP00000497896.1:p.Asp14Tyr D14Y* 0.00009560 VUS PM1, PM2, PP2, BP4
Cirrhosis ENSP00000497896.1:p.Ile513Thr I513T rs772028343 0.00008531 0.00066973 VUS PM2, PP2
Cirrhosis, secondary malignant neoplasm of liver and bile duct, gallstone disease ENSP00000497896.1:p.Asp70Asn D70N7 rs34719006 0.00313900 0.00302678 VUS PM2, PP2, PP3 Conflicting 24,64,69–75
NR1H4 Intrahepatic cholestasis of pregnancy ENSP00000496908.1:p.Asn358His N358H rs149287629 0.00041020 0.00038307 VUS PM2 VUS
ENSP00000496908.1:p.Met173Thr M173T rs61755050 0.00374800 0.00267482 Likely benign PM1, PP3, BS1, BS2, BP6 likely benign 6,76
TJP2 Intrahepatic cholestasis of pregnancy ENSP00000497787.1:p.Thr377Ala T377A rs766748789 0.00000406 0.00047765 VUS PM2, BP4
ENSP00000496791.1:p.Gln105Lys Q105K8 rs41305539 0.05150000 0.12031400 Benign BA1, BP4, BP6, benign 44,77,78
ENSP00000497861.1:p.Arg21His R21H9 rs4493966 0.07416000 0.04555170 Benign BA1, BP4, BP6, benign
Gallstone disease ENSP00000496791.1:p.Gln8Arg Q8R* 0.00009553 VUS PM2, PP3
ENSP00000496791.1:p.Thr68Asn T68N* 0.00019150 VUS PM1, PM2
ENSP00000496791.1:p.Pro152Leu P152L rs754300892 0.00007876 0.00046685 VUS BP4
ENSP00000497787.1:p.Arg178Cys R178C rs199761505 0.00043060 0.00223305 VUS PP3
ENSP00000497787.1:p.Arg255His R255H rs532438219 0.00012990 0.00066947 VUS
ENSP00000497787.1:p.Arg461Pro R461P rs748523814 0.00009746 0.00078125 VUS PP3
ENSP00000496791.1:p.Thr902Met T902M rs774198938 0.00010970 0.00010449 VUS PP3
ENSP00000496791.1:p.Arg1070Lys R1070K* 0.00009564 VUS PM2, BP4 VUS

AF allele frequency, ACMG-AMP American College of Medical Genetics and Genomics and the Association for Molecular Pathology, BP benign supporting, PM pathogenic moderate, PP pathogenic supporting, G&H Genes & Health, LP likely pathogenic, Ref references, VUS variant of unknown significance.

*South Asian specific variant.

#multiple phenotype.

 +Linkage disequilibrium.

^Allele frequency specific to East London Genes & Health cohort.

1T175A, Hom (n) 6, Het (n) 126.

2M677V, Hom (n) 3, Het (n) 99.

3N591S, Hom (n) 99, Het (n) 760.

4M674T, Hom (n) 2, Het (n) 67.

5I577V, Hom (n) 2, Het (n) 61.

6H78Q, Hom (n) 1, Het (n) 47.

7D70N, Hom (n) 1, Het (n) 24.

8Q105K, Hom (n) 76, Het (n) 711.

9R21H, Hom (n) 16, Het (n) 443.