TMC5

Chr 16

transmembrane channel like 5

NCBI Gene: 79838 ENSG00000103534 UniProt: Q6UXY8 OMIM: 617197

The protein is predicted to function as a mechanosensitive ion channel involved in ion transport across cell membranes. Mutations in this gene have been associated with autosomal recessive nonsyndromic hearing loss and potentially other sensory disorders. This gene shows moderate constraint against loss-of-function mutations, suggesting some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

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

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.60

Clinical Summary— TMC5

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Population Constraint (gnomAD)

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

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.60LOEUF

pLI 0.000

Z-score 3.81

OE 0.42 (0.30–0.60)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.65Z-score

OE missense 0.92 (0.86–0.99)

503 obs / 546.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.42 (0.30–0.60)

0≤0.351.4

Missense OE?0.92 (0.86–0.99)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 21 / 50.1Missense obs/exp: 503 / 546.0Syn Z: -0.75

This gene — mechanism propensity

0.81top 10%

GOF

0.73top 25%

LOF

0.2288th %ile

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

DNprediction above median

GOFprediction 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.