TMPRSS3

Summary

TMPRSS3 (transmembrane serine protease 3, HGNC:11877) is a protein-coding gene on chromosome 21q22.3, encoding Transmembrane protease serine 3 (P57727). Probable serine protease that plays a role in hearing.

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.

Source: NCBI Gene 64699 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 668 total — 55 pathogenic, 45 likely-pathogenic
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001256317

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11877
Approved symbol	TMPRSS3
Name	transmembrane serine protease 3
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000160183
Ensembl biotype	protein_coding
OMIM	605511
Entrez	64699

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 18 protein_coding, 2 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000398397, ENST00000398405, ENST00000433957, ENST00000474596, ENST00000476848, ENST00000478680, ENST00000482761, ENST00000644384, ENST00000652415, ENST00000896621, ENST00000896622, ENST00000896623, ENST00000896624, ENST00000896625, ENST00000896626, ENST00000896627, ENST00000896628, ENST00000896629, ENST00000896630, ENST00000896631, ENST00000957272, ENST00000957273

RefSeq mRNA: 4 — MANE Select: NM_001256317 NM_001256317, NM_024022, NM_032404, NM_032405

CCDS: CCDS13686, CCDS42939, CCDS58790

Canonical transcript exons

ENST00000644384 — 13 exons

Exon	Start	End
ENSE00001050357	42389927	42390037
ENSE00003479330	42382065	42382234
ENSE00003494636	42380117	42380212
ENSE00003503535	42385409	42385534
ENSE00003550020	42371890	42372779
ENSE00003564347	42383033	42383198
ENSE00003591562	42395324	42395468
ENSE00003594737	42383970	42384013
ENSE00003597801	42375716	42375868
ENSE00003609993	42376541	42376683
ENSE00003610022	42388403	42388526
ENSE00003625818	42388929	42389045
ENSE00003823045	42395942	42396052

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 94.12.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6573 / max 115.9156, expressed in 135 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190619	0.3677	110
190618	0.1350	45
190617	0.0705	32
190620	0.0465	26
190616	0.0288	6
190615	0.0089	4

Top tissues by expression

263 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	94.12	gold quality
right uterine tube	UBERON:0001302	93.24	gold quality
bronchial epithelial cell	CL:0002328	89.04	gold quality
epithelium of bronchus	UBERON:0002031	88.60	gold quality
epithelial cell of pancreas	CL:0000083	88.15	gold quality
bronchus	UBERON:0002185	88.11	gold quality
mucosa of paranasal sinus	UBERON:0005030	87.25	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	84.95	gold quality
pylorus	UBERON:0001166	83.89	gold quality
gall bladder	UBERON:0002110	81.21	gold quality
nasal cavity epithelium	UBERON:0005384	81.01	silver quality
epithelium of nasopharynx	UBERON:0001951	80.03	gold quality
germinal epithelium of ovary	UBERON:0001304	78.29	gold quality
vena cava	UBERON:0004087	77.41	gold quality
sperm	CL:0000019	77.40	gold quality
parotid gland	UBERON:0001831	77.35	silver quality
nasal cavity mucosa	UBERON:0001826	77.15	gold quality
cardia of stomach	UBERON:0001162	76.91	silver quality
epithelium of mammary gland	UBERON:0003244	76.68	silver quality
saliva-secreting gland	UBERON:0001044	76.50	gold quality
fallopian tube	UBERON:0003889	75.90	gold quality
body of pancreas	UBERON:0001150	75.87	gold quality
cerebellar vermis	UBERON:0004720	75.81	gold quality
mammary duct	UBERON:0001765	75.66	silver quality
minor salivary gland	UBERON:0001830	75.48	gold quality
pancreas	UBERON:0001264	75.34	gold quality
substantia nigra pars reticulata	UBERON:0001966	75.21	silver quality
male germ cell	CL:0000015	75.15	gold quality
inferior vagus X ganglion	UBERON:0005363	74.76	silver quality
lateral globus pallidus	UBERON:0002476	74.65	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.77
E-MTAB-4850	no	511.42
E-GEOD-75688	no	452.51

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

36 targeting TMPRSS3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-187-5P	99.74	70.26	1404
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-1264	99.25	66.81	1317
HSA-MIR-6739-3P	99.22	68.84	1843
HSA-MIR-1245B-5P	98.88	66.55	576
HSA-MIR-3142	98.88	66.09	529
HSA-MIR-873-5P	98.84	66.90	1348

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• missense mutations in autosomal recessive sensorineural deafness (PMID:11462234)
• TMPRSS3 mutations contribute to fewer than 1% of nonsyndromic childhood deafness in Caucasians. (PMID:11907649)
• The TMPRSS3 protein mutated in deafness DFNB8/10 activates the epithelial sodium channel (ENaC) in vitro (PMID:12393794)
• Disruption of the proteolytic activity of TMPRSS3 is tightly correlated with the pathogenesis of hearing loss. (PMID:12920079)
• Identification of mutations in TMPRSS3 in Pakistani families with recessive, nonsyndromic congenital deafness. (PMID:15447792)
• The mutant TMPRSS3 harboring the novel R216L missense mutation within the predicted cleavage site of the protein fails to undergo proteolytic cleavage and is unable to activate ENaC. (PMID:16021470)
• The identification of two novel pathogenic TMPRSS3 mutations (c.646C–>T - R216C; c.916G–>A - A306T) is described in four affected siblings of German origin with postlingual hearing loss, treated by bilateral cochlear implantation with good results. (PMID:17551081)
• TMPRSS3 mutations are not a common cause of hereditary deafness, but the elucidation of its function is nevertheless important for better understanding of hearing [review] (PMID:17981648)
• Six TMPRSS3 variants were found to cosegregate in 10 consanguineous Pakistani families with autosomal recessive non-syndromic hearing impairment. (PMID:21534946)
• Our data suggest that not only the protein truncating mutation p.T70fs has a severe effect but also the amino acid substitutions p.Ala306Thr and p.Val199Met. (PMID:21786053)
• TMPRSS3 gene is not a major contributor to non-syndromic deafness in the Moroccan population. (PMID:22382023)
• Data imply that TMPRSS3-A/D overexpression in EOC is probably due to hypomethylation of their control region. (PMID:22446619)
• Association between TMPRSS3 genotypes and phenotype variants in autosomal recessive nonsyndromic hearing loss. (PMID:23958653)
• Description of the spectrum of mutations in TMPRSS3 in 374 families with autosomal recessive, non-syndromic hearing loss from India. (PMID:24416283)
• The prevalence of TMPRSS3 mutations among Korean postlingual hearing loss is 8.3 %. The p.A306T variant of TMPRSS3 is the common founder allele in Koreans. A novel variant, p.T248M of TMPRSS3, was predicted to have milder pathogenicity. (PMID:24526180)
• Single nucleotide polymorphisms in TMPRSS3 (rs3814903 and rs11203200) are significantly associated with breast cancer risk. (PMID:25029565)
• homozygous mutation TMPRSS3: c.535G>A causes prelingual hearing loss in this Tibetan family (PMID:25474651)
• Low expression levels of hepsin and TMPRSS3 are associated with poor breast cancer survival (PMID:26014348)
• TMPRSS3 mutations seem to be an important cause of autosomal recessive nonsyndromic hearing loss in Slovenia resulting in rather uniform phenotype with profound congenital hearing loss. (PMID:26036852)
• TMPRSS3 expression is an independent prognostic factor for breast cancer patients. Bioinformatic analysis of potential TMPRSS3 binding proteins revealed that TMPRSS3 could be a key regulator of cancer pathways. (PMID:26191247)
• Study demonstrated that TMPRSS3 contributes to ovarian cancer cell proliferation, invasion and metastasis, probably via activation of the ERK1/2 signaling pathway. (PMID:26531004)
• different combinations of TMPRSS3 mutations led to different hearing impairment phenotypes (DFNB8/DFNB10) in the Chinese family. (PMID:28246597)
• In conclusion, TMPRSS3 and TNFRSF11B may have potential prognostic value to be used as tumor biomarkers in breast cancer patients. (PMID:28260080)
• Given that a previous paper suggested TMPRSS3 and GJB2 genes as responsible for a digenic form of hearing loss, our data support and reinforce this hypothesis. (PMID:28263784)
• knockdown of TMPRSS3 inhibits proliferation, migration, and invasion in human nasopharyngeal carcinoma cells through the inactivation of the PI3K/Akt signaling pathway. This study suggests that TMPRSS3 may be a potential therapeutic target for the treatment of nasopharyngeal carcinoma (PMID:28409556)
• Pathogenic variants in the TMPRSS3 gene in a cohort of 2247 subjects with sensorineural hearing loss represented 13 different rare TMPRSS3 variants, nine of which were novel. (PMID:28566687)
• Our results indicate that mutations in TMPRSS3 account for about 4.6% (7/151) of Chinese autosomal recessive nonsyndromic hearing loss cases lacking mutations in SLC26A4 or GJB2 and that the recurrent TMPRSS3 mutation p.Ala306Thr is likely to be a founder mutation. (PMID:28695016)
• For those with a combination of severely pathogenic TMPRSS3 variants, rapid aggravation of the residual hearing should be anticipated and treated accordingly. Our confirmation of the genotype-phenotype correlation of the TMPRSS3 gene may pave the way for the establishment of a personalized auditory rehabilitation. (PMID:29072634)
• TMPRSS3 proteolysis is linked to hair cell sterociliary mechanics and to the actin/microtubule networks that support cell motility and integrity. (PMID:29460002)
• TMPRSS3 contributed to gastric cancer progression via activation of the PI3K/Akt/ERK signaling pathway. (PMID:30142546)
• Pathogenic variants in TMPRSS3 may impact function of the spiral ganglion. (PMID:30242206)
• Complex genomic rearrangement and a novel missense mutation in TMPRSS3 were identified in Chinese cases with prelingual hearing loss. (PMID:31016883)
• TMPRSS3 is an important molecule in the regulation of cell viability and cell apoptosis of HEI-OC1 cells. Its functions are dependent on the circ-Slc41a2, miR-182 and Akt cascade. (PMID:31408246)
• These data provide evidence against TMPRSS3/GJB2 digenic inheritance of hearing loss. (PMID:31412945)
• Novel Mutations in the TMPRSS3 Gene may Contribute to Taiwanese Patients with Nonsyndromic Hearing Loss. (PMID:32235586)
• Mutational analysis and prenatal diagnosis of TMPRSS3 gene in two Chinese families affected with deafness (PMID:32306631)
• Upregulation of the transmembrane protease serine 3 mRNA level in radioresistant colorectal cancer tissues. (PMID:35543030)
• TMPRSS3 expression is limited in spiral ganglion neurons: implication for successful cochlear implantation. (PMID:35961784)
• Genotype-Phenotype Correlations in TMPRSS3 (DFNB10/DFNB8) with Emphasis on Natural History. (PMID:37331337)
• Homozygous Missense Variants in FOXI1 and TMPRSS3 Genes Associated with Non-syndromic Deafness in Moroccan Families. (PMID:37777971)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmprss3b	ENSDARG00000036545
danio_rerio	tmprss3a	ENSDARG00000053315
mus_musculus	Tmprss3	ENSMUSG00000024034
rattus_norvegicus	Tmprss3	ENSRNOG00000001165
drosophila_melanogaster	Sb	FBGN0003319
drosophila_melanogaster	CG17242	FBGN0250841

Paralogs (17): PRSS22 (ENSG00000005001), PRSS21 (ENSG00000007038), TMPRSS11E (ENSG00000087128), HPN (ENSG00000105707), TMPRSS13 (ENSG00000137747), ST14 (ENSG00000149418), TMPRSS11D (ENSG00000153802), TMPRSS15 (ENSG00000154646), TMPRSS5 (ENSG00000166682), TMPRSS7 (ENSG00000176040), TMPRSS9 (ENSG00000178297), TMPRSS2 (ENSG00000184012), TMPRSS11B (ENSG00000185873), TMPRSS6 (ENSG00000187045), TMPRSS11A (ENSG00000187054), TMPRSS11F (ENSG00000198092), PRSS41 (ENSG00000215148)

Protein

Protein identifiers

Transmembrane protease serine 3 — P57727 (reviewed: P57727)

Alternative names: Serine protease TADG-12, Tumor-associated differentially-expressed gene 12 protein

All UniProt accessions (2): P57727, B7WPR2

UniProt curated annotations — full annotation on UniProt →

Function. Probable serine protease that plays a role in hearing. Acts as a permissive factor for cochlear hair cell survival and activation at the onset of hearing and is required for saccular hair cell survival. Activates ENaC (in vitro).

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in many tissues including fetal cochlea. Isoform T is found at increased levels in some carcinomas.

Post-translational modifications. Undergoes autoproteolytic activation.

Disease relevance. Deafness, autosomal recessive, 8 (DFNB8) [MIM:601072] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Has a predicted N-terminal signal sequence, indicating it may be secreted. Expressed in retina, lung, liver, pancreas, placenta and kidney.

Similarity. Belongs to the peptidase S1 family.

Isoforms (6)

UniProt ID	Names	Canonical?
P57727-1	A	yes
P57727-2	B, C
P57727-3	D
P57727-4	T, Truncated, TADG-12V
P57727-5	E
P57727-6	6, TMPRSS3e

RefSeq proteins (4): NP_001243246, NP_076927, NP_115780, NP_115781 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001190	SRCR	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018114	TRYPSIN_HIS	Active_site
IPR023415	LDLR_class-A_CS	Conserved_site
IPR033116	TRYPSIN_SER	Active_site
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR036772	SRCR-like_dom_sf	Homologous_superfamily
IPR043504

Pfam: PF00057, PF00089, PF15494

UniProt features (45 total): sequence variant 12, disulfide bond 10, splice variant 6, sequence conflict 4, domain 3, active site 3, topological domain 2, chain 1, site 1, glycosylation site 1, transmembrane region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P57727-F1	87.09	0.71

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (4): 216–217 (cleavage); 257 (charge relay system); 304 (charge relay system); 401 (charge relay system)

Disulfide bonds (10): 73–85, 79–98, 92–107, 129–194, 142–204, 207–324, 242–258, 338–407, 370–386, 397–425

Glycosylation sites (1): 221

Mutagenesis-validated functional residues (1):

Position	Phenotype
401	fails to undergo proteolytic cleavage and is unable to activate enac.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 124 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_PROTEIN_MATURATION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_1, BLALOCK_ALZHEIMERS_DISEASE_UP, OCT1_03, GOBP_INTRACELLULAR_SODIUM_ION_HOMEOSTASIS, GOBP_SODIUM_ION_HOMEOSTASIS, MASSARWEH_RESPONSE_TO_ESTRADIOL, GOBP_SENSORY_PERCEPTION, GOBP_MONOATOMIC_ION_HOMEOSTASIS, KIM_WT1_TARGETS_12HR_UP, chr21q22, SPIELMAN_LYMPHOBLAST_EUROPEAN_VS_ASIAN_DN, WOOD_EBV_EBNA1_TARGETS_UP

GO Biological Process (3): proteolysis (GO:0006508), intracellular sodium ion homeostasis (GO:0006883), sensory perception of sound (GO:0007605)

GO Molecular Function (6): serine-type endopeptidase activity (GO:0004252), serine-type peptidase activity (GO:0008236), sodium channel regulator activity (GO:0017080), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), neuronal cell body (GO:0043025)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	1
intracellular monoatomic cation homeostasis	1
sodium ion homeostasis	1
sensory perception of mechanical stimulus	1
endopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
sodium channel activity	1
ion channel regulator activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
somatodendritic compartment	1
cell body	1

Protein interactions and networks

STRING

992 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMPRSS3	PJVK	Q0ZLH3	794
TMPRSS3	MYO15A	Q9UKN7	773
TMPRSS3	TMC1	Q8TDI8	770
TMPRSS3	MYO6	Q9UM54	735
TMPRSS3	TMIE	Q8NEW7	731
TMPRSS3	SLC26A4	O43511	729
TMPRSS3	OTOF	Q9HC10	722
TMPRSS3	GJB2	P29033	720
TMPRSS3	LOXHD1	Q8IVV2	706
TMPRSS3	CDH23	Q9H251	702
TMPRSS3	OTOA	Q7RTW8	667
TMPRSS3	MYO7A	P78427	666
TMPRSS3	STRC	Q7RTU9	665
TMPRSS3	PCDH15	Q96QU1	631
TMPRSS3	TPRN	Q4KMQ1	629

IntAct

6 interactions, top by confidence:

A	B	Type	Score
TMPRSS3	TMED7	psi-mi:“MI:0915”(physical association)	0.370
N	RBM47	psi-mi:“MI:0914”(association)	0.350
TMPRSS3	TMEM131L	psi-mi:“MI:0914”(association)	0.350
TMPRSS3	EEF1A1	psi-mi:“MI:0915”(physical association)	0.000
TMPRSS3	RXRA	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (58): TMPRSS3 (Affinity Capture-MS), PPP1R15B (Affinity Capture-MS), CISD2 (Affinity Capture-MS), DCAKD (Affinity Capture-MS), DNAJC18 (Affinity Capture-MS), EPHB4 (Affinity Capture-MS), EIF2AK3 (Affinity Capture-MS), VRK2 (Affinity Capture-MS), UPK3BL (Affinity Capture-MS), RETSAT (Affinity Capture-MS), PDZD8 (Affinity Capture-MS), LRIG3 (Affinity Capture-MS), ALG9 (Affinity Capture-MS), KIAA0319L (Affinity Capture-MS), LRFN3 (Affinity Capture-MS)

ESM2 similar proteins: A6H6T1, A6MFK7, A6MFK8, O15393, O19045, O70169, P00741, P00742, P00749, P04185, P15638, P16227, P18292, P19221, P31394, P33587, P49150, P57727, P70375, P98119, P98121, Q05589, Q14520, Q1L658, Q1L659, Q3UQ41, Q4QXT9, Q56VR3, Q58L93, Q58L94, Q58L95, Q58L96, Q5E9Z2, Q5R537, Q5RF29, Q5U405, Q6AXZ6, Q6AY28, Q6DIV5, Q6L711

Diamond homologs: A0A182C2Z2, B8V7S0, O08762, O60235, P00747, P00760, P00762, P00765, P00766, P00767, P00774, P03951, P03952, P04070, P04813, P05981, P06867, P06871, P06872, P07146, P07338, P07477, P08217, P08426, P08519, P12545, P14272, P15944, P17538, P19799, P20231, P20918, P26262, P27435, P29786, P35033, P40313, P47796, P50342, P56677

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

668 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	55
Likely pathogenic	45
Uncertain significance	159
Likely benign	267
Benign	49

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1075246	NM_001256317.3(TMPRSS3):c.398G>A (p.Trp133Ter)	Pathogenic
1175709	NM_001256317.3(TMPRSS3):c.400A>T (p.Lys134Ter)	Pathogenic
1175710	NM_001256317.3(TMPRSS3):c.646C>T (p.Arg216Cys)	Pathogenic
1175711	NM_001256317.3(TMPRSS3):c.749del (p.Leu250fs)	Pathogenic
1185592	NM_001256317.3(TMPRSS3):c.242C>G (p.Ser81Ter)	Pathogenic
1185654	NM_001256317.3(TMPRSS3):c.147dup (p.Pro50fs)	Pathogenic
1195343	NM_001256317.3(TMPRSS3):c.1206del (p.Leu404fs)	Pathogenic
1363492	NC_000021.8:g.(?43792871)(43815526_?)del	Pathogenic
1454077	NM_001256317.3(TMPRSS3):c.97del (p.Ala33fs)	Pathogenic
1454926	NM_001256317.3(TMPRSS3):c.1033del (p.Ala345fs)	Pathogenic
1509020	NM_001256317.3(TMPRSS3):c.1304G>C (p.Arg435Pro)	Pathogenic
177740	NM_001256317.3(TMPRSS3):c.1189C>T (p.Gln397Ter)	Pathogenic
1909242	NM_001256317.3(TMPRSS3):c.1335_1339dup (p.Met447fs)	Pathogenic
1995820	NM_001256317.3(TMPRSS3):c.1A>G (p.Met1Val)	Pathogenic
2057266	NM_001256317.3(TMPRSS3):c.432del (p.Gln144fs)	Pathogenic
2065963	NM_001256317.3(TMPRSS3):c.775_776del (p.Val259fs)	Pathogenic
2191688	NM_001256317.3(TMPRSS3):c.717C>A (p.Tyr239Ter)	Pathogenic
2498898	NM_001256317.3(TMPRSS3):c.567T>G (p.Tyr189Ter)	Pathogenic
2736991	NM_001256317.3(TMPRSS3):c.1156G>A (p.Ala386Thr)	Pathogenic
2736994	NM_001256317.3(TMPRSS3):c.953-5A>G	Pathogenic
2736995	NM_001256317.3(TMPRSS3):c.783-1G>A	Pathogenic
2736997	NM_001256317.3(TMPRSS3):c.115C>T (p.Gln39Ter)	Pathogenic
2741548	NM_001256317.3(TMPRSS3):c.356_359del (p.Val119fs)	Pathogenic
2765953	NM_001256317.3(TMPRSS3):c.71del (p.Asp23_Leu24insTer)	Pathogenic
2808450	NM_001256317.3(TMPRSS3):c.876C>A (p.Tyr292Ter)	Pathogenic
2835793	NM_001256317.3(TMPRSS3):c.690G>A (p.Trp230Ter)	Pathogenic
2856116	NM_001256317.3(TMPRSS3):c.1017G>A (p.Trp339Ter)	Pathogenic
2882012	NM_001256317.3(TMPRSS3):c.458C>G (p.Ser153Ter)	Pathogenic
2907554	NM_001256317.3(TMPRSS3):c.551T>C (p.Leu184Ser)	Pathogenic
2966618	NM_001256317.3(TMPRSS3):c.1028G>A (p.Trp343Ter)	Pathogenic

SpliceAI

2463 predictions. Top by Δscore:

Variant	Effect	Δscore
21:42376536:CGTA:C	donor_loss	1.0000
21:42376538:TACCT:T	donor_loss	1.0000
21:42376540:C:CA	donor_loss	1.0000
21:42382231:CAAG:C	acceptor_gain	1.0000
21:42388532:CGATG:C	acceptor_gain	1.0000
21:42388533:G:T	acceptor_gain	1.0000
21:42388534:A:C	acceptor_gain	1.0000
21:42388536:G:GC	acceptor_gain	1.0000
21:42388928:CCA:C	donor_gain	1.0000
21:42389041:GTGGA:G	acceptor_gain	1.0000
21:42389042:TGGA:T	acceptor_gain	1.0000
21:42389043:GGA:G	acceptor_gain	1.0000
21:42389044:GA:G	acceptor_gain	1.0000
21:42389046:C:A	acceptor_loss	1.0000
21:42389046:C:CC	acceptor_gain	1.0000
21:42389925:A:AC	donor_gain	1.0000
21:42389925:ACTG:A	donor_gain	1.0000
21:42389925:ACTGC:A	donor_gain	1.0000
21:42389926:C:CT	donor_gain	1.0000
21:42389926:CTG:C	donor_gain	1.0000
21:42389926:CTGC:C	donor_gain	1.0000
21:42389926:CTGCC:C	donor_gain	1.0000
21:42395475:C:CT	acceptor_gain	1.0000
21:42375712:CCA:C	donor_loss	0.9900
21:42375713:CA:C	donor_loss	0.9900
21:42375864:TCCCC:T	acceptor_gain	0.9900
21:42375865:CCCC:C	acceptor_gain	0.9900
21:42375865:CCCCC:C	acceptor_gain	0.9900
21:42375866:CCC:C	acceptor_gain	0.9900
21:42375866:CCCC:C	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000044608 (21:42384103 A>G), RS1000197270 (21:42389123 C>G,T), RS1000433464 (21:42378290 G>C), RS1000473101 (21:42379038 C>A), RS1000493385 (21:42394085 C>A,T), RS1000587646 (21:42387981 G>A,T), RS1000823337 (21:42392817 A>G), RS1001032956 (21:42373168 G>T), RS1001040154 (21:42377317 G>T), RS1001246359 (21:42397391 A>C), RS1001280344 (21:42375034 C>G,T), RS1001382683 (21:42379566 C>G,T), RS1001384464 (21:42397431 G>A,C), RS1001518471 (21:42379343 T>A), RS1001686154 (21:42389354 C>G,T)

Disease associations

OMIM: gene MIM:605511 | disease phenotypes: MIM:601072, MIM:220290, MIM:607197, MIM:193500, MIM:128600

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	Autosomal recessive
autosomal recessive nonsyndromic hearing loss 8	Strong	Autosomal recessive
hearing loss, autosomal recessive	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	AR

Mondo (6): autosomal recessive nonsyndromic hearing loss 8 (MONDO:0010987), hearing loss disorder (MONDO:0005365), hearing loss, autosomal recessive (MONDO:0019588), nonsyndromic genetic hearing loss (MONDO:0019497), Waardenburg syndrome (MONDO:0018094), ear malformation (MONDO:0007500)

Orphanet (5): Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare non-syndromic genetic deafness (Orphanet:87884), Rare genetic deafness (Orphanet:96210), Waardenburg syndrome (Orphanet:3440)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST009309_4	Face memory	4.000000e-06
GCST012442_27	Age-related hearing impairment	8.000000e-08
GCST012442_9	Age-related hearing impairment	8.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004874	memory performance

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D014849	Waardenburg Syndrome	C16.131.077.938
C564609	Deafness, Autosomal Recessive (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	decreases expression, increases expression, increases reaction, affects cotreatment	6
Cyclosporine	affects expression, increases expression	3
(+)-JQ1 compound	decreases expression	2
Resveratrol	affects cotreatment, decreases expression, increases expression	2
Coumestrol	affects cotreatment, increases expression, affects reaction	2
Progesterone	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
OTX015	decreases expression	1
mivebresib	decreases expression	1
dicrotophos	decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
pentanal	decreases expression	1
pinosylvin	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
Zoledronic Acid	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Aldehydes	decreases expression	1
Vehicle Emissions	decreases methylation	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Copper	affects cotreatment, decreases expression	1
Tamoxifen	affects cotreatment, increases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound