AHR

protein-coding

aryl hydrocarbon receptor, the group of Basic helix-loop-helix proteins|PAS domain containing

Gene summary

The protein encoded by this gene is a ligand-activated helix-loop-helix transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons. This receptor has been shown to regulate xenobiotic-metabolizing enzymes such as cytochrome P450. Before ligand binding, the encoded protein is sequestered in the cytoplasm; upon ligand binding, this protein moves to the nucleus and stimulates transcription of target genes. [provided by RefSeq, Sep 2015]

MANE transcript

NM_001621.5

Inheritance

AR, AD

ClinVar variants

P:9U:288B:146

Top phenotype

Retinitis pigmentosa 85;Foveal hypoplasia 3

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr7:16,916,359-17,346,152

External References & Databases

Ensembl (ENSG00000106546)

Transcript & Mutation Effects

hg38 • Region Span ~429.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

retinitis pigmentosa 85MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032689

Submitter: PanelApp Australia

foveal hypoplasiaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044203

Submitter: Ambry Genetics

foveal hypoplasia 3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0975805

Submitter: PanelApp Australia

retinitis pigmentosa 85LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032689

Submitter: G2P

retinitis pigmentosa 85STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032689

Submitter: Labcorp Genetics (formerly Invitae)

retinitis pigmentosaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019200

Submitter: Orphanet

Clinical Genomic Database (CGD)

Retinitis pigmentosa 85;Foveal hypoplasia 3AR

Manifestation: Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 29726989; 31009037; 35188035

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AHR variants in ClinVar

8 Conditions Cataloged

not providedTotal: 451

not specifiedTotal: 93

AHR-related disorderTotal: 13

Retinal dystrophyTotal: 5

Retinitis pigmentosa 85Total: 4

Foveal hypoplasia 3Total: 3

GH-secreting pituitary adenomaTotal: 1

Infantile nystagmus with foveal hypoplasiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001621.5. 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				131 clinvar	3 clinvar	134
missense			285 clinvar	9 clinvar	3 clinvar	297
nonsense	2 clinvar	2 clinvar				4
start loss			1 clinvar			1
frameshift	2 clinvar		1 clinvar			3
splice donor/acceptor (+/-2bp)	2 clinvar	1 clinvar	1 clinvar			4
Total	6	3	288	140	6	443

Highest pathogenic variant AF is 0.000003718237

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001621.5	RefSeq	NP_001612.1	11	MANE Select
ENST00000242057.9	Ensembl	ENSP00000242057.4	11	MANE Select
ENST00000463496.1	Ensembl	ENSP00000436466.1	11	Standard
ENST00000642825.1	Ensembl	ENSP00000495987.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cushing,s syndrome - Homo sapiens (human)
Th17 cell differentiation - Homo sapiens (human)
Integrated Breast Cancer Pathway
Adipogenesis
Aryl Hydrocarbon Receptor

Biological Process

blood vessel development
regulation of transcription, DNA-templated
regulation of transcription by RNA polymerase II
transcription by RNA polymerase II
xenobiotic metabolic process

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
TFIID-class transcription factor complex binding
transcription coactivator binding
DNA binding
DNA-binding transcription factor activity

Cellular Component

nucleus
nucleoplasm
transcription factor complex
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000242057
Coding exons: 11
Length: 47531
Individuals with no LoFs: 125737
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125748
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.735	403	447	0.902	0.0000223	5619
Missense (PolyPhen)		56	101.24	0.55314		1270
Synonymous	-1.01	179	163	1.10	0.00000842	1573
Loss of Function	5.64	2	40.9	0.0489	0.00000238	449

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000062	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ligand-activated transcriptional activator. Binds to the XRE promoter region of genes it activates. Activates the expression of multiple phase I and II xenobiotic chemical metabolizing enzyme genes (such as the CYP1A1 gene). Mediates biochemical and toxic effects of halogenated aromatic hydrocarbons. Involved in cell-cycle regulation. Likely to play an important role in the development and maturation of many tissues. Regulates the circadian clock by inhibiting the basal and circadian expression of the core circadian component PER1. Inhibits PER1 by repressing the CLOCK-ARNTL/BMAL1 heterodimer mediated transcriptional activation of PER1. The heterodimer ARNT:AHR binds to core DNA sequence 5'-TGCGTG-3' within the dioxin response element (DRE) of target gene promoters and activates their transcription (PubMed:28602820). {ECO:0000269|PubMed:10395741, ECO:0000269|PubMed:28602820, ECO:0000269|PubMed:7961644}.;

Recessive Scores

pRec: 0.740

Intolerance Scores

LoFtool: 0.393
RVIS EVS: -0.31
RVIS percentile EVS: 32.23

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.714

Gene Damage Prediction

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