CHRNA3

protein-coding

cholinergic receptor nicotinic alpha 3 subunit, the group of Cholinergic receptors nicotinic subunits

Gene summary

This locus encodes a member of the nicotinic acetylcholine receptor family of proteins. Members of this family of proteins form pentameric complexes comprised of both alpha and beta subunits. This locus encodes an alpha-type subunit, as it contains characteristic adjacent cysteine residues. The encoded protein is a ligand-gated ion channel that likely plays a role in neurotransmission. Polymorphisms in this gene have been associated with an increased risk of smoking initiation and an increased susceptibility to lung cancer. Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2009]

MANE transcript

NM_000743.5

Inheritance

ClinVar variants

P:17U:109B:44

Top phenotype

Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary congenital anomalies of the kidney and urinary tract

gnomAD constraint

pLI —, LoF o/e 0.72

Max pathogenic AF

—

Genomic locus

chr15:78,593,052-78,621,295

External References & Databases

Ensembl (ENSG00000080644)

Transcript & Mutation Effects

hg38 • Region Span ~28.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

urinary bladder, atony ofSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008630

Submitter: Ambry Genetics

urinary bladder, atony ofSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008630

Submitter: G2P

Clinical Genomic Database (CGD)

Bladder dysfunction, autonomic, with impaired pupillary reflex and secondary congenital anomalies of the kidney and urinary tractAR

Manifestation: Neurologic; Renal

Intervention: Renal

Rationale: The condition can involve chronic kidney disease andrecurrent urinary tract infections, and awareness may allow prompt diagnosis and management (of note, surgical management of VUR has not been reported as effective)

Refs: 31708116

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CHRNA3 variants in ClinVar

9 Conditions Cataloged

Urinary bladder, atony ofTotal: 73

not providedTotal: 68

SMOKING AS A QUANTITATIVE TRAIT LOCUS 3Total: 68

Inborn genetic diseasesTotal: 53

CHRNA3-related disorderTotal: 9

Amyotrophic lateral sclerosisTotal: 5

Squamous cell carcinomaTotal: 1

not specifiedTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000743.5. 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			4 clinvar	33 clinvar	4 clinvar	41
missense			103 clinvar	5 clinvar	2 clinvar	110
nonsense	1 clinvar	4 clinvar	1 clinvar			6
start loss		1 clinvar				1
frameshift	4 clinvar	5 clinvar	1 clinvar			10
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar				2
Total	6	11	109	38	6	170

Highest pathogenic variant AF is 0.00024533735

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000743.5	RefSeq	NP_000734.2	6	MANE Select
ENST00000326828.6	Ensembl	ENSP00000315602.5	6	MANE Select
NM_001166694.2	RefSeq	NP_001160166.1	6	Standard
ENST00000348639.7	Ensembl	ENSP00000267951.4	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Neuroactive ligand-receptor interaction - Homo sapiens (human)
Cholinergic synapse - Homo sapiens (human)
Nicotine Pathway (Dopaminergic Neuron), Pharmacodynamics
Nicotine Pathway (Chromaffin Cell), Pharmacodynamics
Nicotine Metabolism Pathway

Biological Process

ion transport
regulation of smooth muscle contraction
signal transduction
activation of transmembrane receptor protein tyrosine kinase activity
chemical synaptic transmission

Molecular Function

extracellular ligand-gated ion channel activity
protein binding
ligand-gated ion channel activity
acetylcholine receptor activity
acetylcholine-gated cation-selective channel activity

Cellular Component

plasma membrane
integral component of plasma membrane
acetylcholine-gated channel complex
postsynaptic density
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000326828
Coding exons: 6
Length: 28244
Individuals with no LoFs: 125642
Homozygous LoFs: 0
Heterozygous LoFs: 106
Defined: 125748
p: 0.000422

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.735	247	282	0.877	0.0000166	3288
Missense (PolyPhen)		119	155.9	0.76331		1816
Synonymous	-2.55	158	122	1.29	0.00000842	1016
Loss of Function	1.09	13	18.0	0.722	7.67e-7	226

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00049	0.00049	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00044	0.00044	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00051	0.00051	rare
South Asian	0.00065	0.00065	rare
Other	0.00082	0.00081	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.;

Recessive Scores

pRec: 0.252

Intolerance Scores

LoFtool: 0.0990
RVIS EVS: -1.11
RVIS percentile EVS: 6.78

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.159

Gene Damage Prediction

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