TMC1

Chr 9ADAR

transmembrane channel like 1

Also known as: DFNA36, DFNB11, DFNB7

NCBI Gene: 117531 ENSG00000165091 UniProt: Q8TDI8 OMIM: 606706

TMC1 encodes a pore-forming subunit of the mechanotransducer channel complex located at stereocilia tips in cochlear hair cells, where it mediates auditory sensory transduction by responding to mechanical tension and transporting calcium and monovalent cations. Mutations cause both progressive postlingual hearing loss and profound prelingual deafness with autosomal recessive inheritance. The gene is extremely intolerant to loss-of-function variants (pLI approaching 1), indicating that complete protein loss is likely incompatible with normal development.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

This gene is considered a member of a gene family predicted to encode transmembrane proteins. The specific function of this gene is unknown; however, it is known to be required for normal function of cochlear hair cells. Mutations in this gene have been associated with progressive postlingual hearing loss and profound prelingual deafness. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Deafness, autosomal dominant 36MIM #606705

Deafness, autosomal recessive 7MIM #600974

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · nonsyndromic genetic hearing loss · AD · ClinGen 2018

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.97

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — TMC1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.97LOEUF

pLI 0.000

Z-score 1.69

OE 0.74 (0.56–0.97)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.86Z-score

OE missense 0.88 (0.81–0.96)

350 obs / 398.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.74 (0.56–0.97)

0≤0.351.4

Missense OE?0.88 (0.81–0.96)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 35 / 47.6Missense obs/exp: 350 / 398.2Syn Z: -0.26

Background carrier burden — how many people carry a rare variant somewhere in TMC1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 64

937 rare PASS variants

Rare truncating (LoF)

1 in 570

181 rare PASS variants

Rare synonymous (reference)

1 in 180

350 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TMC1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 69	1 in 750
South Asian	~43k	1 in 53	1 in 640
Remaining (unassigned)	~30k	1 in 65	1 in 530
European (Finnish)	~27k	1 in 240	1 in 3,000
Admixed American	~22k	1 in 78	1 in 700
African / African American	~21k	1 in 68	1 in 410
East Asian	~20k	1 in 63	1 in 720
Ashkenazi Jewish	~13k	1 in 430	≈ 1 in 3,200
Middle Eastern	~2,884	1 in 61	≈ 1 in 710

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 18 of 20 coding exons well covered in gnomAD exomes; exons 8, 11 marginal. Genomes: 18 of 20 (exons 8, 24 below).? see exons ↓