NR1H3
protein-codingnuclear receptor subfamily 1 group H member 3, the group of Nuclear receptor subfamily 1 group H
Gene summary
The protein encoded by this gene belongs to the NR1 subfamily of the nuclear receptor superfamily. The NR1 family members are key regulators of macrophage function, controlling transcriptional programs involved in lipid homeostasis and inflammation. This protein is highly expressed in visceral organs, including liver, kidney and intestine. It forms a heterodimer with retinoid X receptor (RXR), and regulates expression of target genes containing retinoid response elements. Studies in mice lacking this gene suggest that it may play an important role in the regulation of cholesterol homeostasis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~20.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
No GenCC data available for this gene.
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NR1H3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005693.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 2 | 4 | |||
| missense | 1 | 57 | 4 | 1 | 63 | |
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 1 | 0 | 61 | 6 | 1 | 69 |
Highest pathogenic variant AF is 0.00046090828
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005684.2 | 9 | MANE Select | |
| Ensembl | ENSP00000387946.2 | 9 | MANE Select | |
| RefSeq | NP_001123573.1 | 8 | Standard | |
| RefSeq | NP_001123574.1 | 8 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| nr1h3 | Danio rerio | Structure: ceratohyal cartilage Quality: curved abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Insulin resistance - Homo sapiens (human)
- Non-alcoholic fatty liver disease (NAFLD) - Homo sapiens (human)
- PPAR signaling pathway - Homo sapiens (human)
- Hepatitis C - Homo sapiens (human)
- NHR
Biological Process
- negative regulation of transcription by RNA polymerase II
- transcription initiation from RNA polymerase II promoter
- lipid metabolic process
- multicellular organism development
- negative regulation of macrophage derived foam cell differentiation
Molecular Function
- transcription regulatory region sequence-specific DNA binding
- RNA polymerase II regulatory region sequence-specific DNA binding
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA binding
- steroid hormone receptor activity
Cellular Component
- nuclear chromatin
- nucleus
- nucleoplasm
- cytoplasm
- receptor complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000467728
- Coding exons
- 9
- Length
- 20546
- Individuals with no LoFs
- 125730
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 18
- Defined
- 125748
- p
- 0.0000716
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.30 | 222 | 283 | 0.783 | 0.0000180 | 2915 |
| Missense (PolyPhen) | 63 | 119.64 | 0.52657 | 1226 | ||
| Synonymous | 1.23 | 93 | 109 | 0.850 | 0.00000653 | 899 |
| Loss of Function | 3.61 | 3 | 20.8 | 0.144 | 0.00000100 | 226 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00014 | 0.00014 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.000071 | 0.000070 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Nuclear receptor that exhibits a ligand-dependent transcriptional activation activity (PubMed:19481530, PubMed:25661920). Interaction with retinoic acid receptor (RXR) shifts RXR from its role as a silent DNA-binding partner to an active ligand-binding subunit in mediating retinoid responses through target genes defined by LXRES (By similarity). LXRES are DR4-type response elements characterized by direct repeats of two similar hexanuclotide half-sites spaced by four nucleotides (By similarity). Plays an important role in the regulation of cholesterol homeostasis, regulating cholesterol uptake through MYLIP-dependent ubiquitination of LDLR, VLDLR and LRP8 (PubMed:19481530). Interplays functionally with RORA for the regulation of genes involved in liver metabolism (By similarity). {ECO:0000250|UniProtKB:Q9Z0Y9, ECO:0000269|PubMed:19481530, ECO:0000269|PubMed:25661920}.;
Recessive Scores
- pRec
- 0.542
Intolerance Scores
- LoFtool
- 0.0639
- RVIS EVS
- -0.65
- RVIS percentile EVS
- 16.44
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.999
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |