CHRM3

Chr 1

cholinergic receptor muscarinic 3

Also known as: EGBRS, HM3, PBS, m3AChR

NCBI Gene: 1131 ENSG00000133019 UniProt: P20309

The muscarinic cholinergic receptor 3 mediates cellular responses to acetylcholine including adenylate cyclase inhibition, phosphoinositide breakdown, and potassium channel modulation, and controls smooth muscle contraction and glandular secretion. Mutations cause prune belly syndrome with autosomal recessive inheritance. This gene is highly constrained against loss-of-function variants, indicating its critical functional importance.

ResearchSummary from RefSeq, OMIM, UniProt

The muscarinic cholinergic receptors belong to a larger family of G protein-coupled receptors. The functional diversity of these receptors is defined by the binding of acetylcholine and includes cellular responses such as adenylate cyclase inhibition, phosphoinositide degeneration, and potassium channel mediation. Muscarinic receptors influence many effects of acetylcholine in the central and peripheral nervous system. The muscarinic cholinergic receptor 3 controls smooth muscle contraction and its stimulation causes secretion of glandular tissue. Alternative promoter use and alternative splicing results in multiple transcript variants that have different tissue specificities. [provided by RefSeq, Dec 2016]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.25

Clinical Summary— CHRM3

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 93 VUS of 156 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.25LOEUF

pLI 0.993

Z-score 3.83

OE 0.05 (0.02–0.25)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.96Z-score

OE missense 0.70 (0.63–0.78)

236 obs / 337.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.25)

0≤0.351.4

Missense OE?0.70 (0.63–0.78)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 1 / 19.0Missense obs/exp: 236 / 337.2Syn Z: -0.71

This gene — mechanism propensity

0.6358th %ile

GOF

0.6931th %ile

LOF

0.61top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.25

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

156 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic1

VUS93

Likely Benign44

Benign10

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	1	0	0	2
Likely Pathogenic	1	0	0	0	1
VUS	1	86	4	2	93
Likely Benign	0	5	0	39	44
Benign	0	2	4	4	10
Conflicting	—				2
Total	3	94	8	45	152

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

60 pathogenic / likely-pathogenic (of 84) ClinVar copy-number / structural variants overlap CHRM3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →