GeneBe

TMPRSS6

protein-coding

transmembrane serine protease 6, the group of Type II transmembrane serine proteases

Gene summary

The protein encoded by this gene is a type II transmembrane serine proteinase that is found attached to the cell surface. The encoded protein may be involved in matrix remodeling processes in the liver. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

MANE transcript

NM_001374504.1

Inheritance

AR

ClinVar variants

P:43U:219B:84

Top phenotype

Iron-refractory iron deficiency anemia

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr22:37,065,436-37,109,713

External References & Databases

Ensembl (ENSG00000187045)NCBI Gene (164656)OMIM (609862)HGNC:16517GenCCUniProt (Q8IU80)AlphaFoldClinVar (TMPRSS6)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~44.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

IRIDA syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008788

Submitter: Orphanet

IRIDA syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008788

Submitter: PanelApp Australia

IRIDA syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008788

Submitter: ClinGen

*TMPRSS6* was first reported in relation to autosomal recessive iron-refractory iron deficiency anemia (IRIDA) in 2008 (Finberg et al., PMID: 18408718). IRIDA is characterized by congenital iron deficiency (ID) that is poorly responsive to oral iron treatment. Of note, this gene has also been implicated in autosomal dominant IRIDA due to observations of carriers of truncating variants in this gene showing lower Hb, MCV, and TSAT/hepcidin ratios, which is also supported by mouse models showing that TMPRSS6 haploinsufficiency increases susceptibility to iron deficiency (PMID: 20688966; PMID: 35893046; PMID: 40081160). However, as these AD phenotypes appear to be modulated by environmental factors, the following disease entities have been lumped into one disease entity, iron-refractory iron deficiency anemia (OMIM: 206200), per criteria outlined by the ClinGen Lumping and Splitting Working Group. Several variants (e.g., missense, nonsense, frameshift, indels) have been reported in multiple probands in four publications (PMID: 29895660; PMID: 22581667; PMID: 20232450; PMID: 36261087; PMID: 36690839) and are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by animal models, where recessive, chemically induced mutant mouse phenotypes are characterized by progressive loss of body (but not facial) hair and microcytic anemia (PMID: 18451267). In summary, there is definitive evidence supporting the relationship between TMPRSS6 and autosomal recessive iron-refractory iron deficiency anemia (IRIDA). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen IEM GCEP at the meeting on August 22 (SOP Version 11).

IRIDA syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008788

Submitter: Labcorp Genetics (formerly Invitae)

IRIDA syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008788

Submitter: G2P

IRIDA syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008788

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Iron-refractory iron deficiency anemiaAR

Manifestation: Hematologic

Intervention: Hematologic

Rationale: The condition can involve anemia, which can be severe, and while oral iron therapy (as well as treatment with erythropoetin) alone may not be effective in all individuals (though some individuals have been reported who have been responsive to low-dose oral iron therapy), combination therapy with oral iron and ascorbic acid has been reported as beneficial, and parenteral iron therapy has been reported as partially effective in some individuals

Comments: Variants may also affect hemoglobin levels

Refs: 7229750; 3354554; 8602626; 10524456; 11517621; 18408718; 18596229; 19786206; 21618415; 21643693; 21783390; 22169218; 23180434; 23319530Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TMPRSS6 variants in ClinVar

7 Conditions Cataloged
not providedTotal: 189
Inborn genetic diseasesTotal: 147
Microcytic anemiaTotal: 79
not specifiedTotal: 58
TMPRSS6-related disorderTotal: 45
Iron-refractory iron deficiency anemiaTotal: 38
Abnormality of metabolism/homeostasisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001374504.1. 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.

EffectPLPVUSLBBSum
synonymous
6
clinvar
51
clinvar
3
clinvar
 60
missense
2
clinvar
4
clinvar
207
clinvar
23
clinvar
2
clinvar
 238
nonsense
6
clinvar
7
clinvar
 13
start loss
0
frameshift
9
clinvar
8
clinvar
1
clinvar
 18
splice donor/acceptor (+/-2bp)
3
clinvar
4
clinvar
5
clinvar
5
clinvar
 17
Total2023219795346

Highest pathogenic variant AF is 0.00011711779

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 89 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001374504.1RefSeqNP_001361433.117MANE Select
ENST00000676104.1EnsemblENSP00000501573.117MANE Select
NM_001289000.2RefSeqNP_001275929.118Standard
NM_001289001.2RefSeqNP_001275930.117Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
tmprss6Danio rerio

Structure: nucleate erythrocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Hfe effect on hepcidin production
  • Collagen degradation
  • Extracellular matrix organization
  • Degradation of the extracellular matrix

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • angiogenesis
  • proteolysis
  • cellular iron ion homeostasis
  • extracellular matrix disassembly

Molecular Function

  • metalloendopeptidase activity
  • serine-type endopeptidase activity
  • protein binding

Cellular Component

  • extracellular space
  • plasma membrane
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000346753
Coding exons
18
Length
44128
Individuals with no LoFs
125685
Homozygous LoFs
0
Heterozygous LoFs
63
Defined
125748
p
0.000251
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.2134854980.9730.00003285178
Missense (PolyPhen)180182.410.986811896
Synonymous-0.8982362191.080.00001511617
Loss of Function3.062345.20.5090.00000229474

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000690.00068rare
Latino/Admixed American0.000120.00012rare
Ashkenazi Jewish0.000200.00020rare
East Asian0.000160.00016rare
Finnish00.0absent
European (Non-Finnish)0.000350.00033rare
South Asian0.000100.000098rare
Other0.000330.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Serine protease which hydrolyzes a range of proteins including type I collagen, fibronectin and fibrinogen. Can also activate urokinase-type plasminogen activator with low efficiency. May play a specialized role in matrix remodeling processes in liver. Through the cleavage of HJV, a regulator of the expression of the iron absorption-regulating hormone hepicidin/HAMP, plays a role in iron homeostasis. {ECO:0000269|PubMed:12149247, ECO:0000269|PubMed:18408718, ECO:0000303|PubMed:25156943}.;
Disease
DISEASE: Iron-refractory iron deficiency anemia (IRIDA) [MIM:206200]: Key features include congenital hypochromic microcytic anemia, very low mean corpuscular erythrocyte volume, low transferrin saturation, abnormal iron absorption characterized by no hematologic improvement following treatment with oral iron, and abnormal iron utilization characterized by a sluggish, incomplete response to parenteral iron. {ECO:0000269|PubMed:18408718, ECO:0000269|PubMed:18603562, ECO:0000269|PubMed:19357398, ECO:0000269|PubMed:19592582, ECO:0000269|PubMed:19708871, ECO:0000269|PubMed:19747362, ECO:0000269|PubMed:20232450, ECO:0000269|PubMed:20704562, ECO:0000269|PubMed:21618415, ECO:0000269|PubMed:22581667, ECO:0000269|PubMed:25156943, ECO:0000269|PubMed:25588876}. Note=The disease is caused by mutations affecting the gene represented in this entry. Mutations leading to abrogation of TMPRSS6 activity are associated with IRIDA due to elevated levels of hepcidin, a negative regulator of plasma iron pool (PubMed:20232450). {ECO:0000269|PubMed:20232450}.;

Recessive Scores

pRec
0.145

Intolerance Scores

LoFtool
0.134
RVIS EVS
0.59
RVIS percentile EVS
82.36

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.157

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.