TMPRSS3

Chr 21AR

transmembrane serine protease 3

Also known as: DFNB10, DFNB8, ECHOS1, TADG12

NCBI Gene: 64699 ENSG00000160183 UniProt: P57727 OMIM: 605511

The protein is a transmembrane serine protease that is essential for cochlear and saccular hair cell survival and activation at the onset of hearing, and can activate epithelial sodium channels. Mutations cause autosomal recessive congenital or childhood-onset deafness (DFNB8/DFNB10). The gene is not highly constrained against loss-of-function variants, consistent with its autosomal recessive inheritance pattern.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that belongs to the serine protease family. The encoded protein contains a serine protease domain, a transmembrane domain, an LDL receptor-like domain, and a scavenger receptor cysteine-rich domain. Serine proteases are known to be involved in a variety of biological processes, whose malfunction often leads to human diseases and disorders. This gene was identified by its association with both congenital and childhood onset autosomal recessive deafness. This gene is expressed in fetal cochlea and many other tissues, and is thought to be involved in the development and maintenance of the inner ear or the contents of the perilymph and endolymph. This gene was also identified as a tumor-associated gene that is overexpressed in ovarian tumors. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.121 OMIM phenotype

Clinical Summary— TMPRSS3

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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ClinVar Variants

122 unique Pathogenic / Likely Pathogenic· 160 VUS of 676 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TMPRSS3

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?

1.12LOEUF

pLI 0.000

Z-score 1.10

OE 0.76 (0.53–1.12)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.57Z-score

OE missense 1.10 (1.00–1.21)

284 obs / 258.4 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.76 (0.53–1.12)

0≤0.351.4

Missense OE?1.10 (1.00–1.21)

0≤0.61.4

Synonymous OE?1.25

0≤1.21.6

LoF obs/exp: 19 / 24.9Missense obs/exp: 284 / 258.4Syn Z: -2.12

This gene — mechanism propensity

0.6258th %ile

GOF

0.6737th %ile

LOF

0.3453th %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

676 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic53

Likely Pathogenic69

VUS160

Likely Benign277

Benign51

Conflicting53

Pathogenic

Likely Pathogenic

160

VUS

277

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	35	12	6	0	53
Likely Pathogenic	28	39	2	0	69
VUS	0	113	43	4	160
Likely Benign	0	8	127	142	277
Benign	1	3	45	2	51
Conflicting	—				53
Total	64	175	223	148	663

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

View in ClinVar →

84 pathogenic / likely-pathogenic (of 99) ClinVar copy-number / structural variants overlap TMPRSS3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →