NR1H4

nuclear receptor subfamily 1 group H member 4, the group of Nuclear receptor subfamily 1 group H

Basic information

Region (hg38): 12:100473708-100564414

Links

ENSG00000012504 ∙ NCBI:9971 ∙ OMIM:603826 ∙ HGNC:7967 ∙ Uniprot:Q96RI1 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• cholestasis, progressive familial intrahepatic, 5 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cholestasis, progressive familial intrahepatic 5	AR	Gastrointestinal	The condition involves rapidly progressive, neonatal-onset intralobular cholestasis leading to liver failure and death without liver transplant	Gastrointestinal	26888176

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NR1H4 gene.

• Cholestasis, progressive familial intrahepatic, 5 (4 variants)
• not provided (3 variants)
• Progressive familial intrahepatic cholestasis type 1 (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NR1H4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	14	2	21
missense	1	2	38		1	42
nonsense	3	1				4
start loss			1			1
frameshift	1	2				3
inframe indel	1					1
splice donor/acceptor (+/-2bp)		2				2
splice region			3	2	1	6
non coding		1	2	4	17	24
Total	6	8	46	18	20

Variants in NR1H4

This is a list of pathogenic ClinVar variants found in the NR1H4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-100493065-G-A			Benign (Jun 20, 2021)
12-100493068-C-T			Benign (Jun 20, 2021)
12-100493323-G-T		not specified	Benign (Sep 04, 2015)
12-100493324-A-G		Cholestasis, progressive familial intrahepatic, 5	Uncertain significance (Feb 17, 2022)
12-100493341-T-C			Conflicting classifications of pathogenicity (Jul 03, 2023)
12-100493355-C-T		NR1H4-related disorder	Uncertain significance (Jul 08, 2024)
12-100493370-C-T			Uncertain significance (May 25, 2022)
12-100493402-G-T		Cholestasis, progressive familial intrahepatic, 5	Pathogenic (Oct 10, 2023)
12-100493523-T-C			Benign (Jun 20, 2021)
12-100503383-T-A		NR1H4-related disorder	Uncertain significance (Aug 14, 2023)
12-100503412-G-T		NR1H4-related disorder	Uncertain significance (Sep 23, 2024)
12-100503438-C-T			Benign (Jun 20, 2021)
12-100503449-C-T			Uncertain significance (Apr 01, 2024)
12-100503450-G-A		NR1H4-related disorder	Likely benign (Apr 06, 2021)
12-100503453-G-A			Benign (Jun 20, 2021)
12-100503505-C-G		NR1H4-related disorder	Likely benign (Jun 23, 2021)
12-100503631-A-G			Benign (Jun 20, 2021)
12-100505623-C-G			Uncertain significance (Jul 01, 2021)
12-100510607-TTA-T			Benign (Jun 19, 2021)
12-100510669-AT-A			Benign (Jun 20, 2021)
12-100510766-A-G			Likely benign (May 21, 2022)
12-100510780-G-A			Benign (Dec 12, 2023)
12-100510789-G-T			Likely pathogenic (Nov 24, 2021)
12-100510805-C-T			Uncertain significance (Jul 19, 2017)
12-100510815-G-A		NR1H4-related disorder	Likely benign (Nov 30, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NR1H4	protein_coding	protein_coding	ENST00000551379	9	90706

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000939	0.999	125719	0	28	125747	0.000111

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.54	196	267	0.735	0.0000143	3224
Missense in Polyphen		55	89.379	0.61536		1072
Synonymous	-0.567	103	95.9	1.07	0.00000570	866
Loss of Function	3.03	10	27.0	0.370	0.00000154	310

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000304	0.000293
Ashkenazi Jewish	0.0000992	0.0000992
East Asian	0.000272	0.000272
Finnish	0.00	0.00
European (Non-Finnish)	0.0000928	0.0000879
Middle Eastern	0.000272	0.000272
South Asian	0.0000683	0.0000653
Other	0.000172	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Ligand-activated transcription factor. Receptor for bile acids (BAs) such as chenodeoxycholic acid (CDCA), lithocholic acid, deoxycholic acid (DCA) and allocholic acid (ACA). Plays a essential role in BA homeostasis through the regulation of genes involved in BA synthesis, conjugation and enterohepatic circulation. Also regulates lipid and glucose homeostasis and is involved innate immune response (PubMed:10334992, PubMed:10334993, PubMed:21383957, PubMed:22820415). The FXR-RXR heterodimer binds predominantly to farnesoid X receptor response elements (FXREs) containing two inverted repeats of the consensus sequence 5'- AGGTCA-3' in which the monomers are spaced by 1 nucleotide (IR-1) but also to tandem repeat DR1 sites with lower affinity, and can be activated by either FXR or RXR-specific ligands. It is proposed that monomeric nuclear receptors such as NR5A2/LRH-1 bound to coregulatory nuclear responsive element (NRE) halfsites located in close proximity to FXREs modulate transcriptional activity (By similarity). In the liver activates transcription of the corepressor NR0B2 thereby indirectly inhibiting CYP7A1 and CYP8B1 (involved in BA synthesis) implicating at least in part histone demethylase KDM1A resulting in epigenomic repression, and SLC10A1/NTCP (involved in hepatic uptake of conjugated BAs). Activates transcription of the repressor MAFG (involved in regulation of BA synthesis) (By similarity). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:12754200, PubMed:15471871, PubMed:17895379). Activates transcription of SLC27A5/BACS and BAAT (involved in BA conjugation), ABCB11/BSEP (involved in bile salt export) by directly recruiting histone methyltransferase CARM1, and ABCC2/MRP2 (involved in secretion of conjugated BAs) and ABCB4 (involved in secretion of phosphatidylcholine in the small intestine) (PubMed:10514450, PubMed:15239098, PubMed:16269519). In the intestine activates FGF19 expression and secretion leading to hepatic CYP7A1 repression (PubMed:12815072, PubMed:19085950). The function also involves the coordinated induction of hepatic KLB/beta-klotho expression (By similarity). Regulates transcription of liver UGT2B4 and SULT2A1 involved in BA detoxification; binding to the UGT2B4 promoter seems to imply a monomeric transactivation independent of RXRA (PubMed:12806625, PubMed:16946559). Modulates lipid homeostasis by activating liver NR0B2/SHP-mediated repression of SREBF1 (involved in de novo lipogenesis), expression of PLTP (involved in HDL formation), SCARB1 (involved in HDL hepatic uptake), APOE, APOC1, APOC4, PPARA (involved in beta-oxidation of fatty acids), VLDLR and SDC1 (involved in the hepatic uptake of LDL and IDL remnants), and inhibiting expression of MTTP (involved in VLDL assembly (PubMed:12660231, PubMed:12554753, PubMed:15337761). Increases expression of APOC2 (promoting lipoprotein lipase activity implicated in triglyceride clearance) (PubMed:11579204). Transrepresses APOA1 involving a monomeric competition with NR2A1 for binding to a DR1 element (PubMed:11927623, PubMed:21804189). Also reduces triglyceride clearance by inhibiting expression of ANGPTL3 and APOC3 (both involved in inhibition of lipoprotein lipase) (PubMed:12891557). Involved in glucose homeostasis by modulating hepatic gluconeogenesis through activation of NR0B2/SHP-mediated repression of respective genes. Modulates glycogen synthesis (inducing phosphorylation of glycogen synthase kinase-3) (By similarity). Modulates glucose-stimulated insulin secretion and is involved in insulin resistance (PubMed:20447400). Involved in intestinal innate immunity. Plays a role in protecting the distal small intestine against bacterial overgrowth and preservation of the epithelial barrier (By similarity). Down- regulates inflammatory cytokine expression in several types of immune cells including macrophages and mononuclear cells (PubMed:21242261). Mediates trans-repression of TLR4-induced cytokine expression; the function seems to require its sumoylation and prevents N-CoR nuclear receptor corepressor clearance from target genes such as IL1B and NOS2 (PubMed:19864602). Involved in the TLR9-mediated protective mechanism in intestinal inflammation. Plays an anti-inflammatory role in liver inflammation; proposed to inhibit proinflammatory (but not antiapoptotic) NF-kappa-B signaling) (By similarity). {ECO:0000250|UniProtKB:Q60641, ECO:0000250|UniProtKB:Q62735, ECO:0000269|PubMed:10334992, ECO:0000269|PubMed:10334993, ECO:0000269|PubMed:10514450, ECO:0000269|PubMed:11579204, ECO:0000269|PubMed:11927623, ECO:0000269|PubMed:12554753, ECO:0000269|PubMed:12660231, ECO:0000269|PubMed:12718892, ECO:0000269|PubMed:12754200, ECO:0000269|PubMed:12806625, ECO:0000269|PubMed:12815072, ECO:0000269|PubMed:12891557, ECO:0000269|PubMed:14684751, ECO:0000269|PubMed:15239098, ECO:0000269|PubMed:15337761, ECO:0000269|PubMed:15471871, ECO:0000269|PubMed:16269519, ECO:0000269|PubMed:16946559, ECO:0000269|PubMed:17895379, ECO:0000269|PubMed:18621523, ECO:0000269|PubMed:19085950, ECO:0000269|PubMed:19410460, ECO:0000269|PubMed:19586769, ECO:0000269|PubMed:19864602, ECO:0000269|PubMed:20447400, ECO:0000269|PubMed:21242261, ECO:0000269|PubMed:21804189, ECO:0000269|PubMed:23928191, ECO:0000305|PubMed:21383957, ECO:0000305|PubMed:22820415}.; FUNCTION: Isoform 2: Promotes transcriptional activation of target genes ABCB11/BSEP (inducible by unconjugated CDCA, DCA and ACA), NR0B2/SHP (inducible by unconjugated CDCA DCA and ACA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191}.; FUNCTION: Isoform 4: Promotes transcriptional activation of target genes ABCB11/BSEP (inducible by unconjugated CDCA, ACA and DCA), NR0B2/SHP (inducible by unconjugated CDCA, ACA and DCA), SLC51B/OSTB (inducible by unconjugated CDCA and DCA) and FABP6/IBAP; most efficient isoform compared to isoforms 1 to 3; not inducible by taurine- and glycine-amidated CDCA. {ECO:0000269|PubMed:23928191, ECO:0000269|PubMed:26888176}.
• Disease: DISEASE: Note=May be involved in intrahepatic cholestasis of pregnancy. {ECO:0000305|PubMed:17681172}.; DISEASE: Note=May be involved in cholesterol cholelithiasis. {ECO:0000305|PubMed:17931734}.; DISEASE: Cholestasis, progressive familial intrahepatic, 5 (PFIC5) [MIM:617049]: A disorder characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood. PFIC5 is an autosomal recessive, severe form characterized by onset of intralobular cholestasis in the neonatal period. {ECO:0000269|PubMed:26888176}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Bile secretion - Homo sapiens (human);NHR;Drug Induction of Bile Acid Pathway;Farnesoid X Receptor Pathway;Nuclear Receptors Meta-Pathway;Nuclear Receptors in Lipid Metabolism and Toxicity;Chemical Compounds to monitor Proteins;Steatosis AOP;Gene expression (Transcription);Phase I - Functionalization of compounds;Generic Transcription Pathway;Metabolism of lipids;Nuclear Receptor transcription pathway;RNA Polymerase II Transcription;Endogenous sterols;Cytochrome P450 - arranged by substrate type;Biological oxidations;Metabolism;Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol;Synthesis of bile acids and bile salts via 27-hydroxycholesterol;Synthesis of bile acids and bile salts;Recycling of bile acids and salts;Bile acid and bile salt metabolism;Metabolism of steroids;RXR and RAR heterodimerization with other nuclear receptor (Consensus)

Recessive Scores

• pRec: 0.655

Intolerance Scores

• loftool: 0.126
• rvis_EVS: 0.19
• rvis_percentile_EVS: 67.03

Haploinsufficiency Scores

• pHI: 0.542
• hipred: Y
• hipred_score: 0.750

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.969

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Nr1h4
• Phenotype: cellular phenotype; homeostasis/metabolism phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; growth/size/body region phenotype; skeleton phenotype; immune system phenotype; digestive/alimentary phenotype; neoplasm; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;nitrogen catabolite activation of transcription from RNA polymerase II promoter;cellular glucose homeostasis;transcription initiation from RNA polymerase II promoter;lipid metabolic process;inflammatory response;cell-cell junction assembly;Notch signaling pathway;multicellular organism development;bile acid metabolic process;negative regulation of tumor necrosis factor-mediated signaling pathway;regulation of low-density lipoprotein particle clearance;bile acid and bile salt transport;cell differentiation;intracellular receptor signaling pathway;negative regulation of NF-kappaB transcription factor activity;negative regulation of interleukin-1 production;negative regulation of interleukin-2 production;negative regulation of interleukin-6 production;toll-like receptor 4 signaling pathway;toll-like receptor 9 signaling pathway;regulation of urea metabolic process;histone H3-R17 methylation;cellular triglyceride homeostasis;positive regulation of insulin secretion involved in cellular response to glucose stimulus;bile acid signaling pathway;intracellular bile acid receptor signaling pathway;cholesterol homeostasis;defense response to bacterium;negative regulation of apoptotic process;negative regulation of I-kappaB kinase/NF-kappaB signaling;steroid hormone mediated signaling pathway;innate immune response;positive regulation of transcription by RNA polymerase II;positive regulation of insulin receptor signaling pathway;negative regulation of inflammatory response;lipid homeostasis;fatty acid homeostasis;regulation of insulin secretion involved in cellular response to glucose stimulus;regulation of bile acid biosynthetic process;negative regulation of bile acid biosynthetic process;cellular response to lipopolysaccharide;cellular response to fatty acid;cellular response to organonitrogen compound;negative regulation of monocyte chemotactic protein-1 production;interleukin-17 secretion;regulation of cholesterol metabolic process;negative regulation of interferon-gamma secretion;positive regulation of adipose tissue development;negative regulation of tumor necrosis factor secretion;positive regulation of phosphatidic acid biosynthetic process;positive regulation of glutamate metabolic process;positive regulation of ammonia assimilation cycle
• Cellular component: nucleus;nucleoplasm;nuclear euchromatin;RNA polymerase II transcription factor complex
• Molecular function: transcription regulatory region sequence-specific DNA binding;RNA polymerase II regulatory region sequence-specific DNA binding;RNA polymerase II distal enhancer sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA-binding transcription factor activity;steroid hormone receptor activity;transcription coactivator activity;transcription corepressor activity;nuclear receptor activity;protein binding;transcription factor binding;zinc ion binding;nuclear receptor binding;nuclear receptor transcription coactivator activity;bile acid binding;signaling receptor activity;bile acid receptor activity;sequence-specific DNA binding;retinoid X receptor binding;chenodeoxycholic acid binding