NR1I2

protein-coding

nuclear receptor subfamily 1 group I member 2, the group of Nuclear receptor subfamily 1 group I

Gene summary

This gene product belongs to the nuclear receptor superfamily, members of which are transcription factors characterized by a ligand-binding domain and a DNA-binding domain. The encoded protein is a transcriptional regulator of the cytochrome P450 gene CYP3A4, binding to the response element of the CYP3A4 promoter as a heterodimer with the 9-cis retinoic acid receptor RXR. It is activated by a range of compounds that induce CYP3A4, including dexamethasone and rifampicin. Several alternatively spliced transcripts encoding different isoforms, some of which use non-AUG (CUG) translation initiation codon, have been described for this gene. Additional transcript variants exist, however, they have not been fully characterized. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003889.4

Inheritance

ClinVar variants

U:71B:10

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr3:119,780,484-119,818,487

External References & Databases

Ensembl (ENSG00000144852)

Transcript & Mutation Effects

hg38 • Region Span ~38.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

pediatric lymphomaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0003659

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NR1I2 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 72

not providedTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003889.4. 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				3 clinvar	5 clinvar	8
missense			71 clinvar	2 clinvar		73
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	71	5	5	81

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003889.4	RefSeq	NP_003880.3	8	MANE Select
ENST00000393716.8	Ensembl	ENSP00000377319.3	8	MANE Select
NM_022002.3	RefSeq	NP_071285.1	9	Standard
NM_033013.3	RefSeq	NP_148934.1	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Carbamazepine Pathway, Pharmacokinetics
Taxane Pathway, Pharmacokinetics
Metformin Pathway, Pharmacodynamic
Etoposide Pathway, Pharmacokinetics/Pharmacodynamics
NHR

Biological Process

transcription initiation from RNA polymerase II promoter
xenobiotic metabolic process
signal transduction
multicellular organism development
steroid metabolic process

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
steroid hormone receptor activity

Cellular Component

nucleus
nucleoplasm
nuclear body
intermediate filament cytoskeleton
RNA polymerase II transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000337940
Coding exons: 9
Length: 38002
Individuals with no LoFs: 125685
Homozygous LoFs: 0
Heterozygous LoFs: 63
Defined: 125748
p: 0.000251

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.622	307	278	1.10	0.0000175	3115
Missense (PolyPhen)		121	106.4	1.1372		1234
Synonymous	-1.06	121	107	1.13	0.00000663	911
Loss of Function	0.975	15	19.7	0.763	9.03e-7	245

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00062	0.00062	rare
Latino/Admixed American	0.000089	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00054	0.00054	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00020	0.00020	rare
South Asian	0.00039	0.00039	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Nuclear receptor that binds and is activated by variety of endogenous and xenobiotic compounds. Transcription factor that activates the transcription of multiple genes involved in the metabolism and secretion of potentially harmful xenobiotics, drugs and endogenous compounds. Activated by the antibiotic rifampicin and various plant metabolites, such as hyperforin, guggulipid, colupulone, and isoflavones. Response to specific ligands is species-specific. Activated by naturally occurring steroids, such as pregnenolone and progesterone. Binds to a response element in the promoters of the CYP3A4 and ABCB1/MDR1 genes. {ECO:0000269|PubMed:11297522, ECO:0000269|PubMed:11668216, ECO:0000269|PubMed:12578355, ECO:0000269|PubMed:18768384, ECO:0000269|PubMed:19297428, ECO:0000269|PubMed:9727070}.;

Recessive Scores

pRec: 0.650

Intolerance Scores

RVIS EVS: -0.55
RVIS percentile EVS: 19.86

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.996

Gene Damage Prediction

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