TMC3

Chr 15

transmembrane channel like 3

NCBI Gene: 342125 ENSG00000188869 UniProt: Q7Z5M5

TMC3 encodes a predicted mechanosensitive ion channel component located in the plasma membrane that facilitates ion transport across cell membranes. The gene is not highly constrained against loss-of-function variants (pLI near 0, LOEUF >1), and no established human disease associations have been reported in the provided data. The molecular function and clinical significance of this gene remain to be fully characterized.

ResearchSummary from RefSeq, UniProt

Predicted to enable mechanosensitive monoatomic ion channel activity. Predicted to be involved in monoatomic ion transmembrane transport. Predicted to be located in plasma membrane. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.03

Clinical Summary— TMC3

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

171 VUS of 197 total submissions

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

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.03LOEUF

pLI 0.000

Z-score 1.35

OE 0.79 (0.61–1.03)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.51Z-score

OE missense 0.94 (0.88–1.01)

582 obs / 618.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.79 (0.61–1.03)

0≤0.351.4

Missense OE?0.94 (0.88–1.01)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 39 / 49.2Missense obs/exp: 582 / 618.0Syn Z: 0.33

This gene — mechanism propensity

0.74top 25%

GOF

0.74top 25%

LOF

0.3452th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

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.

ClinVar Variant Classifications

197 submitted variants in ClinVar

ClinVar

Classification Summary

VUS171

Likely Benign8

Benign1

171

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	0	171	0	171
Likely Benign	0	7	1	8
Benign	1	0	0	1
Total	1	178	1	180

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 25) ClinVar copy-number / structural variants overlap TMC3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →