NR1H4 disease: rapidly progressing neonatal intrahepatic cholestasis and early death

Table 1 NR1H4 variants and the results of in silico pathogenicity prediction

Patients	cDNA change (NM_005123.4)	Protein change (NP_005114.1)	Parental origin	gnomAD	gnomAD EAS	MuT	SIFT	REVEL	MutPred	PROVEAN	SpliceAI	varSEAK	ACMG grade
P1	c.688 C > T	p.Arg230Ter (het)	maternal	0 / 1 / 251,458	0 / 0 / 18,394	NMD	/	/	/	/	N	N	P: PVS1 + PM2_S + PP4
	c.505T > A	p.Cys169Ser (het)	paternal	-	-	D	D	D	D	D	N	N	LP: PP3 + PM2_S + PP4 + PM3
P2	c.1235T > C	p.Leu412Pro (hom)	n.a.	-	-	D	D	D	D	D	N	N	LP: PP3 + PM2_S + PP4
P3	c.1066 + 1G > A	/	maternal	-	-	D	/	/	/	/	D	D	P: PVS1 + PM2_S + PP4
	c.527G > A	p.Arg176Gln	paternal	0 / 1 / 31,410	0 / 0 / 1560	D	D	D	D	D	N	N	LP: PP3 + PM2_S + PP4 + PM3

gnomAD and gnomAD EAS: frequencies of corresponding mutations respectively in all populations and in East Asian populations of gnomAD (http://gnomad-old.broadinstitute.org/); MuT: MutationTaster (http://www.mutationtaster.org); SIFT: Sorting Intolerant From Tolerant (http://provean.jcvi.org/index.php); REVEL: Rare Exome Variant Ensemble Learner (https://sites.google.com/site/revelgenomics/); MutPred: http://mutpred.mutdb.org/; PROVEAN: Protein Variation Effect Analyzer (http://provean.jcvi.org/index.php; SpliceAI: https://spliceailookup.broadinstitute.org/; varSEAK, https://varseak.bio/index.php?hascredit=false; ACMG, the American College of Medical Genetics and Genomics (http://acmg.cbgc.org.cn); P1-3, patient 1–3; NMD, nonsense-mediated mRNA decay; /, not applicable; N, no effect; P, pathogenic; PVS1, null variants includes nonsense, frameshift, canonical ± 1 or 2 splice sites, initiation codon, single exon or multi-exon deletion variants; PM2_S, variants are absent in gnomAD; PP4, clinical features matches the known clinical phenotype of NR1H4 disease; -, variants were absent in gnomAD and gnomAD EAS; D, disease-causing; LP, likely pathogenic; PM3, variants occur in trans; n.a., not available

ISSN: 1750-1172