TMPRSS2

protein-coding

transmembrane serine protease 2, the group of Type II transmembrane serine proteases|Scavenger receptor cysteine rich domain containing

Gene summary

This gene encodes a protein that belongs to the serine protease family. The encoded protein contains a type II transmembrane domain, a receptor class A domain, a scavenger receptor cysteine-rich domain and a protease domain. Serine proteases are known to be involved in many physiological and pathological processes. This gene was demonstrated to be up-regulated by androgenic hormones in prostate cancer cells and down-regulated in androgen-independent prostate cancer tissue. The protease domain of this protein is thought to be cleaved and secreted into cell media after autocleavage. This protein also facilitates entry of viruses into host cells by proteolytically cleaving and activating viral envelope glycoproteins. Viruses found to use this protein for cell entry include Influenza virus and the human coronaviruses HCoV-229E, MERS-CoV, SARS-CoV and SARS-CoV-2 (COVID-19 virus). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2020]

MANE transcript

NM_005656.4

Inheritance

—

ClinVar variants

U:26B:18

Top phenotype

TMPRSS2-related disorder

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr21:41,464,300-41,531,116

External References & Databases

Ensembl (ENSG00000184012)

Transcript & Mutation Effects

hg38 • Region Span ~66.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMPRSS2 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 19

not providedTotal: 13

TMPRSS2-related disorderTotal: 3

EBV-positive nodal T- and NK-cell lymphomaTotal: 2

Prostate cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005656.4. 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			2 clinvar	3 clinvar	5 clinvar	10
missense			17 clinvar	7 clinvar	3 clinvar	27
nonsense						0
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			6 clinvar			6
Total	0	0	26	10	8	44

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005656.4	RefSeq	NP_005647.3	13	MANE Select
ENST00000332149.10	Ensembl	ENSP00000330330.5	13	MANE Select
NM_001135099.1	RefSeq	NP_001128571.1	14	Standard
NM_001382720.1	RefSeq	NP_001369649.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Influenza A - Homo sapiens (human)
Prostate cancer - Homo sapiens (human)
Transcriptional misregulation in cancer - Homo sapiens (human)
Coregulation of Androgen receptor activity
Regulation of Androgen receptor activity

Biological Process

proteolysis
receptor-mediated endocytosis
protein autoprocessing
positive regulation of viral entry into host cell

Molecular Function

serine-type endopeptidase activity
scavenger receptor activity
protein binding
serine-type peptidase activity

Cellular Component

plasma membrane
integral component of plasma membrane
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000398585
Coding exons: 14
Length: 66566
Individuals with no LoFs: 125696
Homozygous LoFs: 0
Heterozygous LoFs: 52
Defined: 125748
p: 0.000207

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.399	303	323	0.938	0.0000197	3428
Missense (PolyPhen)		108	126.63	0.85288		1357
Synonymous	0.758	132	144	0.919	0.0000109	1013
Loss of Function	1.81	20	30.9	0.648	0.00000132	358

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.000059	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.000092	0.000046	rare
European (Non-Finnish)	0.00030	0.00030	rare
South Asian	0.00020	0.00020	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine protease that proteolytically cleaves and activates the viral spike glycoproteins which facilitate virus- cell membrane fusions; spike proteins are synthesized and maintained in precursor intermediate folding states and proteolysis permits the refolding and energy release required to create stable virus-cell linkages and membrane coalescence. Facilitates human SARS coronavirus (SARS-CoV) infection via two independent mechanisms, proteolytic cleavage of ACE2, which might promote viral uptake, and cleavage of coronavirus spike glycoprotein which activates the glycoprotein for cathepsin L- independent host cell entry. Proteolytically cleaves and activates the spike glycoproteins of human coronavirus 229E (HCoV-229E) and human coronavirus EMC (HCoV-EMC) and the fusion glycoproteins F0 of Sendai virus (SeV), human metapneumovirus (HMPV), human parainfluenza 1, 2, 3, 4a and 4b viruses (HPIV). Essential for spread and pathogenesis of influenza A virus (strains H1N1, H3N2 and H7N9); involved in proteolytic cleavage and activation of hemagglutinin (HA) protein which is essential for viral infectivity. {ECO:0000269|PubMed:21068237, ECO:0000269|PubMed:21325420, ECO:0000269|PubMed:23536651, ECO:0000269|PubMed:23966399, ECO:0000269|PubMed:24027332, ECO:0000269|PubMed:24227843}.;

Recessive Scores

pRec: 0.195

Intolerance Scores

LoFtool: 0.166
RVIS EVS: 0.31
RVIS percentile EVS: 72.75

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0651

Gene Damage Prediction

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