NR1I3

protein-coding

nuclear receptor subfamily 1 group I member 3, the group of Nuclear receptor subfamily 1 group I

Gene summary

This gene encodes a member of the nuclear receptor superfamily, and is a key regulator of xenobiotic and endobiotic metabolism. The protein binds to DNA as a monomer or a heterodimer with the retinoid X receptor and regulates the transcription of target genes involved in drug metabolism and bilirubin clearance, such as cytochrome P450 family members. Unlike most nuclear receptors, this transcriptional regulator is constitutively active in the absence of ligand but is regulated by both agonists and inverse agonists. Ligand binding results in translocation of this protein to the nucleus, where it activates or represses target gene transcription. These ligands include bilirubin, a variety of foreign compounds, steroid hormones, and prescription drugs. In addition to drug metabolism, the CAR protein is also reported to regulate genes involved in glucose metabolism, lipid metabolism, cell proliferation, and circadian clock regulation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2020]

MANE transcript

NM_005122.5

Inheritance

ClinVar variants

U:74B:13

Top phenotype

NR1I3-related disorder

gnomAD constraint

pLI —, LoF o/e 0.74

Max pathogenic AF

—

Genomic locus

chr1:161,229,666-161,238,244

External References & Databases

Ensembl (ENSG00000143257)

Transcript & Mutation Effects

hg38 • Region Span ~8.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual disabilityLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: G2P

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NR1I3 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 51

not providedTotal: 14

NR1I3-related disorderTotal: 3

Kleefstra syndrome 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005122.5. 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			6 clinvar	5 clinvar	1 clinvar	12
missense			60 clinvar	7 clinvar		67
nonsense			1 clinvar			1
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	0	0	74	12	1	87

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 100 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005122.5	RefSeq	NP_005113.1	8	MANE Select
ENST00000367983.9	Ensembl	ENSP00000356962.5	8	MANE Select
NM_001077469.3	RefSeq	NP_001070937.1	8	Standard
NM_001077470.3	RefSeq	NP_001070938.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Carbamazepine Pathway, Pharmacokinetics
NHR
Nuclear Receptors
Drug Induction of Bile Acid Pathway
Constitutive Androstane Receptor Pathway

Biological Process

transcription initiation from RNA polymerase II promoter
signal transduction
multicellular organism development
cell differentiation
androgen receptor signaling pathway

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 transcription activator activity, RNA polymerase II-specific
DNA binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol
cytoskeleton

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367980
Coding exons: 8
Length: 8637
Individuals with no LoFs: 125601
Homozygous LoFs: 0
Heterozygous LoFs: 147
Defined: 125748
p: 0.000585

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.811	177	210	0.843	0.0000120	2325
Missense (PolyPhen)		55	69.138	0.79551		794
Synonymous	0.0325	79	79.4	0.995	0.00000400	719
Loss of Function	1.06	14	19.0	0.738	0.00000116	184

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0016	0.0016	notable
Latino/Admixed American	0.00080	0.00078	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00066	0.00065	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00060	0.00060	rare
South Asian	0.00027	0.00026	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds and transactivates the retinoic acid response elements that control expression of the retinoic acid receptor beta 2 and alcohol dehydrogenase 3 genes. Transactivates both the phenobarbital responsive element module of the human CYP2B6 gene and the CYP3A4 xenobiotic response element.;

Recessive Scores

pRec: 0.348

Intolerance Scores

LoFtool: 0.0107
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: 0.945

Gene Damage Prediction

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