TMPRSS6

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

Basic information

Region (hg38): 22:37065435-37109713

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.

• Microcytic anemia (104 variants)
• not provided (104 variants)
• Inborn genetic diseases (28 variants)
• Iron-refractory iron deficiency anemia (22 variants)
• not specified (11 variants)
• TMPRSS6-related condition (3 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.

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.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			7	6	13	26
missense		3	73	7	8	91
nonsense	3	2				5
start loss						0
frameshift		2	2			4
inframe indel						0
splice donor/acceptor (+/-2bp)			2	3	1	6
splice region			3	2	1	6
non coding			11	9	27	47
Total	3	7	95	25	49

Highest pathogenic variant AF is 0.0000788

Variants in TMPRSS6

This is a list of pathogenic ClinVar variants found in the TMPRSS6 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
22-37065500-G-C		Microcytic anemia	Benign (Jan 13, 2018)
22-37065504-G-T		Microcytic anemia	Likely benign (Jan 13, 2018)
22-37065534-A-G		Microcytic anemia	Benign (Jan 12, 2018)
22-37065577-G-C		Microcytic anemia	Benign (Jan 13, 2018)
22-37065581-G-A		Microcytic anemia	Uncertain significance (Jan 12, 2018)
22-37065669-G-A		Microcytic anemia	Likely benign (Jan 13, 2018)
22-37065777-A-C		Microcytic anemia	Uncertain significance (Jan 12, 2018)
22-37065829-A-T		Microcytic anemia	Uncertain significance (Apr 27, 2017)
22-37065868-A-T		Microcytic anemia	Uncertain significance (Jan 13, 2018)
22-37065940-G-A		Microcytic anemia	Uncertain significance (Jan 12, 2018)
22-37065994-G-A		Microcytic anemia	Benign (Jan 13, 2018)
22-37066008-C-A		Microcytic anemia	Likely benign (Jan 13, 2018)
22-37066045-A-G		Microcytic anemia	Uncertain significance (Jan 13, 2018)
22-37066056-C-T		Microcytic anemia	Uncertain significance (Jan 12, 2018)
22-37066082-A-C			Likely pathogenic (Mar 01, 2022)
22-37066115-C-T		Microcytic anemia	Uncertain significance (Mar 02, 2018)
22-37066117-G-A			Uncertain significance (Dec 19, 2021)
22-37066133-C-T		not specified • Microcytic anemia	Conflicting classifications of pathogenicity (Jan 29, 2024)
22-37066137-G-A			Likely benign (May 20, 2023)
22-37066142-A-G		Inborn genetic diseases	Uncertain significance (Mar 07, 2016)
22-37066150-C-T		Inborn genetic diseases	Uncertain significance (Aug 12, 2021)
22-37066156-C-T		Inborn genetic diseases	Uncertain significance (Nov 17, 2023)
22-37066170-G-A		Microcytic anemia	Benign (Jan 18, 2024)
22-37066211-T-G		Inborn genetic diseases	Uncertain significance (Oct 27, 2023)
22-37066217-C-G			Uncertain significance (Feb 25, 2022)

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