TMPRSS3

protein-coding

transmembrane serine protease 3, the group of Scavenger receptor cysteine rich domain containing|Type II transmembrane serine proteases

Gene summary

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]

Previous symbols:

DFNB10
DFNB8

MANE transcript

NM_001256317.3

Inheritance

ClinVar variants

P:132U:127B:172

Top phenotype

Deafness, autosomal recessive 10; Deafness, autosomal recessive 8

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr21:42,371,887-42,396,091

External References & Databases

Ensembl (ENSG00000160183)

Transcript & Mutation Effects

hg38 • Region Span ~24.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The TMPRSS3 gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 8/16/2016. This association was made using case-level data only. At least 8 missense, frameshift, and splice-site variants have been reported in humans. TMPRSS3 was first associated with this disease in humans as early as 2001 (Scott et al.). Association is seen in at least 9 probands in 5 publications (11137999, 28695016, 25474651, 26036852, 11907649). Variants in this gene segregated with disease in multiple additional family members. More evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease association is supported by a mouse model, expression studies, and functional assays. In summary, TMPRSS3 is definitively associated with autosomal recessive nonsyndromic hearing loss. This classification was approved by the ClinGen Hearing Loss Working Group on 8/22/2017.

autosomal recessive nonsyndromic hearing loss 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010987

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010987

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 10; Deafness, autosomal recessive 8AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 11137999; 11907649; 16021470; 23226338

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMPRSS3 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 467

Autosomal recessive nonsyndromic hearing loss 8Total: 136

not specifiedTotal: 91

Inborn genetic diseasesTotal: 67

TMPRSS3-related disorderTotal: 61

Rare genetic deafnessTotal: 14

Hearing impairmentTotal: 13

Hearing loss, autosomal recessiveTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001256317.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	155 clinvar	1 clinvar	160
missense	8 clinvar	56 clinvar	119 clinvar	16 clinvar		199
nonsense	13 clinvar	11 clinvar				24
start loss	2 clinvar		1 clinvar			3
frameshift	13 clinvar	9 clinvar				22
splice donor/acceptor (+/-2bp)	5 clinvar	15 clinvar	3 clinvar			23
Total	41	91	127	171	1	431

Highest pathogenic variant AF is 0.0019458074

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 41 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001256317.3	RefSeq	NP_001243246.1	12	MANE Select
ENST00000644384.2	Ensembl	ENSP00000494414.1	12	MANE Select
NM_024022.4	RefSeq	NP_076927.1	12	Standard
NM_032404.3	RefSeq	NP_115780.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

proteolysis
cellular sodium ion homeostasis
receptor-mediated endocytosis
sensory perception of sound

Molecular Function

serine-type endopeptidase activity
scavenger receptor activity
sodium channel regulator activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
integral component of membrane
neuronal cell body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000291532
Coding exons: 12
Length: 24957
Individuals with no LoFs: 125558
Homozygous LoFs: 0
Heterozygous LoFs: 190
Defined: 125748
p: 0.000756

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.565	284	258	1.10	0.0000163	2944
Missense (PolyPhen)		103	104	0.99042		1109
Synonymous	-2.12	141	112	1.25	0.00000844	899
Loss of Function	1.10	19	24.9	0.763	0.00000125	289

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0.00099	0.00099	rare
East Asian	0.00054	0.00054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.0013	0.0013	notable
South Asian	0.000098	0.000098	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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 (By similarity). Activates ENaC (in vitro). {ECO:0000250, ECO:0000269|PubMed:12393794}.;
Disease: DISEASE: 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. {ECO:0000269|PubMed:11424922, ECO:0000269|PubMed:11462234, ECO:0000269|PubMed:11907649, ECO:0000269|PubMed:12393794, ECO:0000269|PubMed:15447792, ECO:0000269|PubMed:16021470}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.105

Intolerance Scores

LoFtool: 0.154
RVIS EVS: -0.28
RVIS percentile EVS: 33.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.847

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	High	Medium	High
Cancer	High	Medium	High