TMPRSS6

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

Basic information

Region (hg38): 22:37065436-37109713

Links

ENSG00000187045

∙ NCBI:164656 ∙ OMIM:609862 ∙ HGNC:16517 ∙ Uniprot:Q8IU80 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

IRIDA syndrome (Definitive), mode of inheritance: AR
IRIDA syndrome (Strong), mode of inheritance: AR
IRIDA syndrome (Strong), mode of inheritance: AR
IRIDA syndrome (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Iron-refractory iron deficiency anemia	AR	Hematologic	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	Hematologic	7229750; 3354554; 8602626; 10524456; 11517621; 18408718; 18596229; 19786206; 21618415; 21643693; 21783390; 22169218; 23180434; 23319530
Variants may also affect hemoglobin levels

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TMPRSS6 gene.

not_provided (140 variants)
Inborn_genetic_diseases (121 variants)
Microcytic_anemia (80 variants)
Iron-refractory_iron_deficiency_anemia (35 variants)
TMPRSS6-related_disorder (27 variants)
not_specified (4 variants)
Abnormality_of_metabolism/homeostasis (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TMPRSS6 gene is commonly pathogenic or not. These statistics are base on transcript: NM_001374504.1. Only rare variants are included in the table.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUSVUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	24 clinvar	10 clinvar	40
missense	2 clinvar	3 clinvar	169 clinvar	19 clinvar	5 clinvar	198
nonsense	6 clinvar	5 clinvar				11
start loss						0
frameshift	8 clinvar	3 clinvar	1 clinvar			12
splice donor/acceptor (+/-2bp)	3 clinvar	2 clinvar	2 clinvar	5 clinvar		12
Total	19	13	178	48	15

Highest pathogenic variant AF is 0.00011711779

Loading clinvar variants...

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TMPRSS6	protein_coding	protein_coding	ENST00000346753	18	44128

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.14e-10	0.999	125685	0	63	125748	0.000251

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.213	485	498	0.973	0.0000328	5178
Missense in Polyphen		180	182.41	0.98681		1896
Synonymous	-0.898	236	219	1.08	0.0000151	1617
Loss of Function	3.06	23	45.2	0.509	0.00000229	474

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000807	0.000795
Ashkenazi Jewish	0.000199	0.000198
East Asian	0.000163	0.000163
Finnish	0.00	0.00
European (Non-Finnish)	0.000346	0.000334
Middle Eastern	0.000163	0.000163
South Asian	0.000100	0.0000980
Other	0.000330	0.000326

dbNSFP

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}.;
Pathway: Hfe effect on hepcidin production;Collagen degradation;Extracellular matrix organization;Degradation of the extracellular matrix (Consensus)

Recessive Scores

pRec: 0.145

Intolerance Scores

loftool: 0.134
rvis_EVS: 0.59
rvis_percentile_EVS: 82.36

Haploinsufficiency Scores

pHI: 0.115
hipred: Y
hipred_score: 0.587
ghis: 0.444

Essentials

essential_gene_CRISPR: N
essential_gene_CRISPR2: N
essential_gene_gene_trap: N
gene_indispensability_pred: N
gene_indispensability_score: 0.157

Gene Damage Prediction

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

Mouse Genome Informatics

Gene name: Tmprss6
Phenotype: homeostasis/metabolism phenotype; endocrine/exocrine gland phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); reproductive system phenotype; growth/size/body region phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); hematopoietic system phenotype; digestive/alimentary phenotype; immune system phenotype; liver/biliary system phenotype;

Zebrafish Information Network

Gene name: tmprss6
Affected structure: nucleate erythrocyte
Phenotype tag: abnormal
Phenotype quality: decreased amount

Gene ontology

Biological process: negative regulation of transcription by RNA polymerase II;angiogenesis;proteolysis;cellular iron ion homeostasis;extracellular matrix disassembly;extracellular matrix organization;negative regulation of BMP signaling pathway;collagen catabolic process;membrane protein proteolysis;intracellular signal transduction;fibrinolysis;negative regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;iron ion homeostasis;self proteolysis
Cellular component: extracellular space;plasma membrane;integral component of membrane
Molecular function: metalloendopeptidase activity;serine-type endopeptidase activity;protein binding