Table 3 Non-synonymous variants identified in the five gene candidates associated with a cholestatic phenotype in the Genes and Health cohort.

From: Rare variant contribution to cholestatic liver disease in a South Asian population in the United Kingdom

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	^{23,24,25,26,27,28,29,30}
		ENSP00000496956.1:p.Thr175Ala	T175A¹	rs58238559	0.01155000	0.01315030	LB	PM1, PP2, PP3, BS1, BS2, BP6	Benign/likely benign	^{3,12,23,25,26,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43}
	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	^{12,43,44,45,46,47,48,49,50,51,52}
		ENSP00000497931.1:p.Asn591Ser	N591S³	rs11568367	0.01436000	0.12647200	Benign	PM1, PP2, BA1, BP6	Benign	^{3,12,28,36,46,52,53,54,55,56,57,58,59,60,61}
		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	ENSP00000497896.1:p.Arg384His	R384H#	rs2271260	0.00026400	0.00048040	VUS	PM2, PP2, BP6		³
	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	^{52,63,64,65,66,67,68}
		ENSP00000497896.1:p.Ile577Val	I577V+⁵	rs3745078	0.00467800	0.00628992	Benign	PP2, BA1, BP6	Benign	^{52,63,64,65,66,68}
		ENSP00000497896.1:p.His78Gln	H78Q+⁶	rs3745079	0.00421800	0.00495751	Benign	PP2, BP4,BP6, BS1, BS2	Benign	^{52,63,64,65,66,68}
		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	^{24,64,69,70,71,72,73,74,75}
NR1H4	Intrahepatic cholestasis of pregnancy	ENSP00000496908.1:p.Asn358His	N358H	rs149287629	0.00041020	0.00038307	VUS	PM2	VUS
NR1H4	Intrahepatic cholestasis of pregnancy	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.

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Table 3 Non-synonymous variants identified in the five gene candidates associated with a cholestatic phenotype in the Genes and Health cohort.

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