TMPRSS5

Summary

TMPRSS5 (transmembrane serine protease 5, HGNC:14908) is a protein-coding gene on chromosome 11q23.2, encoding Transmembrane protease serine 5 (Q9H3S3). May play a role in hearing.

This gene encodes a protein that belongs to the serine protease family. Serine proteases are known to be involved in many physiological and pathological processes. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 80975 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Limited, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 114 total
• MANE Select transcript: NM_030770

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14908
Approved symbol	TMPRSS5
Name	transmembrane serine protease 5
Location	11q23.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC141886, MGC148044
Ensembl gene	ENSG00000166682
Ensembl biotype	protein_coding
OMIM	606751
Entrez	80975

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000299882, ENST00000536856, ENST00000538091, ENST00000538770, ENST00000538955, ENST00000539732, ENST00000540540, ENST00000544476, ENST00000544634, ENST00000545265, ENST00000545412, ENST00000545579, ENST00000645981, ENST00000884651

RefSeq mRNA: 5 — MANE Select: NM_030770 NM_001288749, NM_001288750, NM_001288751, NM_001288752, NM_030770

CCDS: CCDS44735, CCDS73390, CCDS73391, CCDS73392, CCDS73393

Canonical transcript exons

ENST00000299882 — 13 exons

Exon	Start	End
ENSE00001105635	113690231	113690373
ENSE00001105641	113689765	113689917
ENSE00001314399	113700066	113700168
ENSE00002243401	113687550	113688274
ENSE00003517561	113696858	113696971
ENSE00003532880	113693071	113693249
ENSE00003554578	113699595	113699693
ENSE00003623027	113690841	113690939
ENSE00003627853	113706222	113706308
ENSE00003629566	113697283	113697418
ENSE00003635172	113698905	113699027
ENSE00003642656	113695400	113695443
ENSE00003644852	113694478	113694640

Expression profiles

Bgee: expression breadth ubiquitous, 166 present calls, max score 96.43.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8259 / max 108.5483, expressed in 175 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
122351	0.5661	141
122352	0.2598	105

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibial nerve	UBERON:0001323	96.43	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.94	gold quality
spinal cord	UBERON:0002240	87.39	gold quality
amygdala	UBERON:0001876	87.17	gold quality
caudate nucleus	UBERON:0001873	87.13	gold quality
putamen	UBERON:0001874	86.67	gold quality
minor salivary gland	UBERON:0001830	86.25	gold quality
sural nerve	UBERON:0015488	85.95	gold quality
nucleus accumbens	UBERON:0001882	85.82	gold quality
trigeminal ganglion	UBERON:0001675	85.22	gold quality
dorsal root ganglion	UBERON:0000044	84.23	gold quality
saliva-secreting gland	UBERON:0001044	84.04	gold quality
mouth mucosa	UBERON:0003729	83.28	gold quality
right frontal lobe	UBERON:0002810	82.65	gold quality
substantia nigra	UBERON:0002038	81.61	gold quality
Brodmann (1909) area 9	UBERON:0013540	81.50	gold quality
midbrain	UBERON:0001891	80.87	gold quality
anterior cingulate cortex	UBERON:0009835	80.72	gold quality
cingulate cortex	UBERON:0003027	80.69	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.36	silver quality
ventricular zone	UBERON:0003053	79.77	gold quality
pancreatic ductal cell	CL:0002079	79.73	silver quality
hypothalamus	UBERON:0001898	79.32	gold quality
corpus callosum	UBERON:0002336	79.04	gold quality
telencephalon	UBERON:0001893	78.75	gold quality
Ammon’s horn	UBERON:0001954	78.61	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.47	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	78.08	gold quality
forebrain	UBERON:0001890	77.94	gold quality
brain	UBERON:0000955	77.43	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.26

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA3

miRNA regulators (miRDB)

24 targeting TMPRSS5, 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-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-6877-3P	98.98	65.83	560
HSA-MIR-6819-3P	98.95	65.57	572
HSA-MIR-3179	98.22	65.90	1445
HSA-MIR-6842-3P	98.07	66.33	1325
HSA-MIR-6502-3P	97.86	65.43	569
HSA-MIR-215-3P	97.02	68.01	1209
HSA-MIR-5192	96.89	63.35	879
HSA-MIR-873-3P	96.84	66.09	786
HSA-MIR-616-3P	96.82	66.99	784
HSA-MIR-342-3P	96.44	67.48	1344
HSA-MIR-3918	96.13	64.65	1300
HSA-MIR-4522	95.76	66.23	742
HSA-MIR-627-5P	95.51	66.80	509
HSA-MIR-12115	94.19	66.37	738

Literature-anchored findings (GeneRIF, showing 1)

• The purified IGF-binding protein-5 (IGFBP-5) protease fraction secreted by cultured human osteoblasts has been characterized as ADAM9. (PMID:12484779)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmprss5	ENSDARG00000087717
mus_musculus	Tmprss5	ENSMUSG00000032268
rattus_norvegicus	Tmprss5	ENSRNOG00000008058
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), TMPRSS3 (ENSG00000160183), TMPRSS7 (ENSG00000176040), TMPRSS9 (ENSG00000178297), TMPRSS2 (ENSG00000184012), TMPRSS11B (ENSG00000185873), TMPRSS6 (ENSG00000187045), TMPRSS11A (ENSG00000187054), TMPRSS11F (ENSG00000198092), PRSS41 (ENSG00000215148)

Protein

Protein identifiers

Transmembrane protease serine 5 — Q9H3S3 (reviewed: Q9H3S3)

Alternative names: Spinesin

All UniProt accessions (10): A0A0G2JKU3, F5GX83, F5GXT6, F5GYA3, F5H0U3, F5H2M3, F5H8D2, G5EA43, G5EA47, Q9H3S3

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in hearing.

Subcellular location. Cell membrane.

Tissue specificity. Brain-specific. Predominantly expressed in neurons, in their axons, and at the synapses of motoneurons in the spinal cord.

Disease relevance. Defects in TMPRSS5 may be a cause of deafness.

Similarity. Belongs to the peptidase S1 family.

RefSeq proteins (5): NP_001275678, NP_001275679, NP_001275680, NP_001275681, NP_110397* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001190	SRCR	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018114	TRYPSIN_HIS	Active_site
IPR033116	TRYPSIN_SER	Active_site
IPR036772	SRCR-like_dom_sf	Homologous_superfamily
IPR043504

Pfam: PF00089, PF15494

UniProt features (31 total): disulfide bond 7, sequence variant 7, glycosylation site 5, active site 3, topological domain 2, domain 2, chain 1, site 1, transmembrane region 1, sequence conflict 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H3S3-F1	79.62	0.52

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): 217–218 (cleavage); 258 (charge relay system); 308 (charge relay system); 405 (charge relay system)

Disulfide bonds (7): 135–196, 148–206, 209–328, 243–259, 342–411, 374–390, 401–429

Glycosylation sites (5): 163, 170, 195, 319, 375

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 50 (showing top): GOBP_PROTEIN_MATURATION, IRF1_Q6, GOBP_PROTEOLYSIS, GOCC_CELL_BODY, GOCC_SOMATODENDRITIC_COMPARTMENT, IRF2_01, GOMF_PEPTIDASE_ACTIVITY, GOBP_PROTEIN_PROCESSING, GOBERT_OLIGODENDROCYTE_DIFFERENTIATION_DN, FORTSCHEGGER_PHF8_TARGETS_DN, IRF1_01, PKCA_DN.V1_DN, GSE10240_CTRL_VS_IL17_STIM_PRIMARY_BRONCHIAL_EPITHELIAL_CELLS_UP, SOX10_TARGET_GENES, GSE11864_CSF1_VS_CSF1_IFNG_IN_MAC_DN

GO Biological Process (1): proteolysis (GO:0006508)

GO Molecular Function (4): serine-type endopeptidase activity (GO:0004252), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (3): plasma membrane (GO:0005886), neuronal cell body (GO:0043025), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein metabolic process	1
endopeptidase activity	1
serine-type peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
membrane	1
cell periphery	1
somatodendritic compartment	1
cell body	1
cellular anatomical structure	1

Protein interactions and networks

STRING

750 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMPRSS5	TMCO5A	Q8N6Q1	502
TMPRSS5	HJV	Q6ZVN8	475
TMPRSS5	NCOA7	Q8NI08	433
TMPRSS5	ZNF696	Q9H7X3	429
TMPRSS5	TMEM278	A6NKF7	420
TMPRSS5	LYG2	Q86SG7	394
TMPRSS5	KRABD3	A5PL33	392
TMPRSS5	CLEC2A	Q6UVW9	389
TMPRSS5	ZW10	O43264	364
TMPRSS5	PXDC1	Q5TGL8	363
TMPRSS5	KCNJ12	Q14500	355
TMPRSS5	OR9Q2	Q8NGE9	354
TMPRSS5	HAMP	P81172	351
TMPRSS5	HTR3B	O95264	350
TMPRSS5	SSC5D	A1L4H1	350
TMPRSS5	RPS15	P11174	350

IntAct

5 interactions, top by confidence:

A	B	Type	Score
TMPRSS5	N4BP2L2	psi-mi:“MI:0915”(physical association)	0.400
TFAP2A	TMPRSS5	psi-mi:“MI:0915”(physical association)	0.370
TMPRSS5	SLC25A14	psi-mi:“MI:0914”(association)	0.350
TMPRSS5	CLGN	psi-mi:“MI:0914”(association)	0.350

BioGRID (50): TMEM214 (Affinity Capture-MS), YBEY (Affinity Capture-MS), TOR3A (Affinity Capture-MS), CDC42SE2 (Affinity Capture-MS), ARF5 (Affinity Capture-MS), BDH1 (Affinity Capture-MS), N4BP2L2 (Affinity Capture-MS), N4BP2L2 (Affinity Capture-MS), TMPRSS5 (Affinity Capture-RNA), TMPRSS5 (Biochemical Activity), SLC25A14 (Affinity Capture-MS), MCL1 (Affinity Capture-MS), N4BP2L2 (Affinity Capture-MS), NR2F2 (Affinity Capture-MS), GPR126 (Affinity Capture-MS)

ESM2 similar proteins: A0EQL2, A2AJ76, A2AJA7, A6H8M9, A8T650, A8T682, A8T688, A8T6A6, D3ZLH5, F1QVU0, O08628, O75173, O88839, P04278, P08514, P08689, P0DV84, P15196, P20701, P29376, P32970, P38570, P60882, P80012, P97497, P97793, Q13444, Q15113, Q5RFQ8, Q5TM20, Q61398, Q63191, Q6UXC1, Q7Z304, Q7Z442, Q7Z7M0, Q8BNJ2, Q8CG85, Q8K1S7, Q8NBP7

Diamond homologs: A0A126GUP6, A0A182C2Z2, A0A1S4H5M5, A8JUP7, B5U2W0, B7YZU2, F5HKX0, O15393, O35453, O60235, O60259, O97366, P00774, P03951, P03952, P05049, P05981, P08419, P09871, P10323, P13582, P14272, P21902, P23578, P25155, P26262, P28175, P29293, P31394, P33587, P35035, P35036, P35037, P35039, P35041, P35045, P35046, P35047, P40313, P48038

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	49
Likely benign	20
Benign	36

Top pathogenic / likely-pathogenic (0)

SpliceAI

1884 predictions. Top by Δscore:

Variant	Effect	Δscore
11:113696973:T:C	acceptor_gain	0.9900
11:113696978:A:T	acceptor_gain	0.9900
11:113696973:T:TC	acceptor_gain	0.9800
11:113696977:C:CT	acceptor_gain	0.9800
11:113700064:A:AC	donor_gain	0.9800
11:113700065:C:CC	donor_gain	0.9800
11:113689933:A:C	acceptor_gain	0.9700
11:113695391:ATGAC:A	donor_loss	0.9700
11:113695392:TGACT:T	donor_loss	0.9700
11:113695393:GACTC:G	donor_loss	0.9700
11:113695394:ACTCA:A	donor_loss	0.9700
11:113695395:CT:C	donor_loss	0.9700
11:113695396:T:TA	donor_loss	0.9700
11:113695397:C:CC	donor_loss	0.9700
11:113695399:C:CT	donor_loss	0.9700
11:113696972:C:CC	acceptor_gain	0.9700
11:113698934:T:TA	donor_gain	0.9700
11:113689928:C:T	acceptor_gain	0.9600
11:113690249:T:TA	donor_gain	0.9600
11:113697277:TGTTA:T	donor_loss	0.9600
11:113697278:GTTAC:G	donor_loss	0.9600
11:113697279:TTACC:T	donor_loss	0.9600
11:113697280:TA:T	donor_loss	0.9600
11:113697281:A:G	donor_loss	0.9600
11:113697282:C:CT	donor_loss	0.9600
11:113697414:AGATA:A	acceptor_gain	0.9600
11:113697416:ATA:A	acceptor_gain	0.9600
11:113689928:C:CT	acceptor_gain	0.9500
11:113693683:C:CT	acceptor_gain	0.9500
11:113696989:A:AC	acceptor_gain	0.9500

AlphaMissense

2963 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:113694570:C:A	W231C	0.992
11:113694570:C:G	W231C	0.992
11:113689852:G:C	S424R	0.991
11:113689852:G:T	S424R	0.991
11:113689854:T:G	S424R	0.991
11:113690863:C:A	W347C	0.990
11:113690863:C:G	W347C	0.990
11:113689849:C:A	W425C	0.989
11:113689849:C:G	W425C	0.989
11:113690268:C:G	C390S	0.988
11:113690269:A:T	C390S	0.988
11:113694572:A:G	W231R	0.986
11:113694572:A:T	W231R	0.986
11:113690316:C:G	C374S	0.985
11:113690317:A:T	C374S	0.985
11:113693112:T:A	D308V	0.984
11:113689783:C:A	W447C	0.983
11:113689783:C:G	W447C	0.983
11:113690878:G:C	C342W	0.983
11:113689838:C:G	C429S	0.982
11:113689839:A:T	C429S	0.982
11:113689863:C:A	G421W	0.982
11:113690880:A:G	C342R	0.982
11:113690268:C:T	C390Y	0.981
11:113690879:C:G	C342S	0.981
11:113690880:A:T	C342S	0.981
11:113689898:A:G	L409P	0.980
11:113689862:C:T	G421E	0.979
11:113689913:T:A	D404V	0.979
11:113690235:C:G	C401S	0.978

dbSNP variants (sampled 300 via entrez): RS1000091826 (11:113688952 G>A), RS1000110055 (11:113704470 A>G), RS1000167637 (11:113695123 T>G), RS1000442940 (11:113704822 C>T), RS1000636630 (11:113687602 C>A), RS1000677045 (11:113702275 G>A), RS1000708155 (11:113694902 T>A,C), RS1000878310 (11:113699997 G>A), RS1001115299 (11:113706033 T>C), RS1001123003 (11:113687861 A>ACCTCCCAGCAC), RS1001239962 (11:113692417 C>T), RS1001271008 (11:113692147 C>A), RS1001347302 (11:113699350 C>T), RS1001500973 (11:113689637 C>T), RS1001504103 (11:113691898 T>C)

Disease associations

OMIM: gene MIM:606751 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Limited	Autosomal dominant

Mondo (1): nonsyndromic genetic hearing loss (MONDO:0019497)

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST002666_7	Interferon alpha levels in systemic lupus erythematosus	3.000000e-06
GCST004146_26	Chronic lymphocytic leukemia	2.000000e-11
GCST005024_33	Pursuit maintenance gain	5.000000e-08
GCST005024_5	Pursuit maintenance gain	7.000000e-07
GCST005028_8	Pursuit maintenance gain in psychotic disorders	4.000000e-07
GCST006945_22	Feeling guilty	2.000000e-08
GCST006946_9	Worry too long after an embarrassing experience	1.000000e-09
GCST007576_287	Chronotype	2.000000e-09
GCST008163_288	Height	2.000000e-06
GCST008478_38	Neurological blood protein biomarker levels	1.000000e-43
GCST011701_3	Smoking status (current vs mixed)	3.000000e-11
GCST011702_3	Smoking cessation	2.000000e-08
GCST011704_12	Smoking status (current vs never)	6.000000e-12
GCST90013423_2	Age-related nuclear cataracts	3.000000e-10

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0006517	interferon alpha measurement
EFO:0008433	pursuit maintenance gain measurement
EFO:0009595	guilt measurement
EFO:0009589	worry measurement
EFO:0008328	chronotype measurement
EFO:0006527	smoking status measurement
EFO:0004319	smoking cessation

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
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

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
aristolochic acid I	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sodium arsenite	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
CGP 52608	affects binding, increases reaction	1
Fulvestrant	affects cotreatment, increases methylation	1
Benzo(a)pyrene	decreases methylation	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Copper Sulfate	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations