TEK

TEK receptor tyrosine kinase, the group of CD molecules|Receptor tyrosine kinases|Fibronectin type III domain containing|Immunoglobulin like domain containing

Basic information

Region (hg38): 9:27109140-27230174

Previous symbols: [ "VMCM" ]

Links

ENSG00000120156 ∙ NCBI:7010 ∙ OMIM:600221 ∙ HGNC:11724 ∙ Uniprot:Q02763 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• multiple cutaneous and mucosal venous malformations (Definitive), mode of inheritance: AD
• multiple cutaneous and mucosal venous malformations (Strong), mode of inheritance: AD
• multiple cutaneous and mucosal venous malformations (Supportive), mode of inheritance: AD
• congenital glaucoma (Supportive), mode of inheritance: AD
• glaucoma 3, primary congenital, E (Strong), mode of inheritance: AD
• multiple cutaneous and mucosal venous malformations (Strong), mode of inheritance: AD
• TEK-related primary glaucoma (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Glaucoma 3, primary congenital, E; Venous malformations, multiple cutaneous and mucosal	AD	Cardiovascular; Ophthalmologic	In Glaucoma 3, primary congenital, E, individuals can have infant/early-childhood ocular hypertension, and optic neuropathy, resulting in vision loss, aand awareness may allow early diagnosis, surveillance, and management; In Venous malformations, multiple cutaneous and mucosal, some individuals have venous malformations (including vascular neoplasms) within internal organs that could lead to severe sequelae, and cardiac malformations have also been described in a few individuals	Cardiovascular; Ophthalmologic	7833915; 7783168; 8980225; 10369874; 19888299; 27270174

ClinVar

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

• not provided (176 variants)
• Multiple cutaneous and mucosal venous malformations (113 variants)
• Inborn genetic diseases (40 variants)
• Glaucoma 3, primary congenital, E (19 variants)
• not specified (9 variants)
• Abnormal cardiovascular system morphology (8 variants)
• Segmental undergrowth associated with venous malformation without capillary component (5 variants)
• Vascular malformation (4 variants)
• TEK-related condition (3 variants)
• Bockenheimer syndrome (1 variants)
• Venous malformation (1 variants)
• Blue rubber bleb nevus (1 variants)
• Acute myeloid leukemia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TEK 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			8	17	21	46
missense	6	7	70	14	11	108
nonsense	4	4				8
start loss						0
frameshift	2	7	1			10
inframe indel			1			1
splice donor/acceptor (+/-2bp)		2				2
splice region			3	4	2	9
non coding			14	7	87	108
Total	12	20	94	38	119

Highest pathogenic variant AF is 0.0000131

Variants in TEK

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

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

Position	Type	Phenotype	Significance	ClinVar
9-27109166-A-G		Multiple cutaneous and mucosal venous malformations	Likely benign (Jun 14, 2016)
9-27109237-A-G		Multiple cutaneous and mucosal venous malformations	Uncertain significance (Jan 13, 2018)
9-27109265-A-G		Multiple cutaneous and mucosal venous malformations	Uncertain significance (Jan 13, 2018)
9-27109315-T-TG		Multiple cutaneous and mucosal venous malformations	Benign (Jun 14, 2016)
9-27109495-G-A		Multiple cutaneous and mucosal venous malformations	Uncertain significance (Jan 12, 2018)
9-27109570-G-A		Multiple cutaneous and mucosal venous malformations	Benign (Jan 12, 2018)
9-27109602-A-C		Multiple cutaneous and mucosal venous malformations	Benign (Jan 12, 2018)
9-27109622-G-A		Glaucoma 3, primary congenital, E	Uncertain significance (Jan 03, 2022)
9-27109628-G-T			Uncertain significance (Dec 28, 2021)
9-27109640-C-G		Inborn genetic diseases	Uncertain significance (Dec 03, 2021)
9-27157837-T-C			Likely benign (Oct 20, 2023)
9-27157864-T-C			Uncertain significance (Mar 10, 2022)
9-27157916-C-T		Multiple cutaneous and mucosal venous malformations	Benign (Jan 12, 2024)
9-27157927-G-GC		Glaucoma 3, primary congenital, E	Likely pathogenic (Jan 03, 2022)
9-27157936-A-T		Inborn genetic diseases	Uncertain significance (Aug 02, 2021)
9-27157991-G-A		TEK-related disorder	Likely benign (Nov 25, 2019)
9-27158010-G-A		Inborn genetic diseases	Uncertain significance (Sep 07, 2022)
9-27158011-T-C			Benign (Jul 31, 2023)
9-27158012-G-A		Multiple cutaneous and mucosal venous malformations	Benign (Sep 05, 2023)
9-27158022-T-C		Inborn genetic diseases	Uncertain significance (Aug 17, 2021)
9-27158034-G-A		Inborn genetic diseases	Uncertain significance (Nov 09, 2021)
9-27158045-G-T		Multiple cutaneous and mucosal venous malformations • Inborn genetic diseases	Conflicting classifications of pathogenicity (Dec 21, 2023)
9-27158048-AG-GC			Uncertain significance (Nov 22, 2017)
9-27158049-G-C		Inborn genetic diseases	Uncertain significance (Jun 02, 2023)
9-27158087-A-C		Multiple cutaneous and mucosal venous malformations • Inborn genetic diseases • TEK-related disorder	Conflicting classifications of pathogenicity (Nov 22, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TEK	protein_coding	protein_coding	ENST00000380036	23	121035

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	0.00000209	125726	0	11	125737	0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.35	501	593	0.844	0.0000335	7372
Missense in Polyphen		141	260.27	0.54175		3143
Synonymous	-3.20	278	218	1.28	0.0000129	2150
Loss of Function	6.49	5	58.6	0.0854	0.00000316	699

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000289	0.0000289
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000793	0.0000791
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Tyrosine-protein kinase that acts as cell-surface receptor for ANGPT1, ANGPT2 and ANGPT4 and regulates angiogenesis, endothelial cell survival, proliferation, migration, adhesion and cell spreading, reorganization of the actin cytoskeleton, but also maintenance of vascular quiescence. Has anti-inflammatory effects by preventing the leakage of proinflammatory plasma proteins and leukocytes from blood vessels. Required for normal angiogenesis and heart development during embryogenesis. Required for post- natal hematopoiesis. After birth, activates or inhibits angiogenesis, depending on the context. Inhibits angiogenesis and promotes vascular stability in quiescent vessels, where endothelial cells have tight contacts. In quiescent vessels, ANGPT1 oligomers recruit TEK to cell-cell contacts, forming complexes with TEK molecules from adjoining cells, and this leads to preferential activation of phosphatidylinositol 3-kinase and the AKT1 signaling cascades. In migrating endothelial cells that lack cell-cell adhesions, ANGT1 recruits TEK to contacts with the extracellular matrix, leading to the formation of focal adhesion complexes, activation of PTK2/FAK and of the downstream kinases MAPK1/ERK2 and MAPK3/ERK1, and ultimately to the stimulation of sprouting angiogenesis. ANGPT1 signaling triggers receptor dimerization and autophosphorylation at specific tyrosine residues that then serve as binding sites for scaffold proteins and effectors. Signaling is modulated by ANGPT2 that has lower affinity for TEK, can promote TEK autophosphorylation in the absence of ANGPT1, but inhibits ANGPT1-mediated signaling by competing for the same binding site. Signaling is also modulated by formation of heterodimers with TIE1, and by proteolytic processing that gives rise to a soluble TEK extracellular domain. The soluble extracellular domain modulates signaling by functioning as decoy receptor for angiopoietins. TEK phosphorylates DOK2, GRB7, GRB14, PIK3R1; SHC1 and TIE1. {ECO:0000269|PubMed:12816861, ECO:0000269|PubMed:14665640, ECO:0000269|PubMed:15284220, ECO:0000269|PubMed:15851516, ECO:0000269|PubMed:18366015, ECO:0000269|PubMed:18425119, ECO:0000269|PubMed:18425120, ECO:0000269|PubMed:19223473, ECO:0000269|PubMed:20651738, ECO:0000269|PubMed:9204896}.
• Disease: DISEASE: Dominantly inherited venous malformations (VMCM) [MIM:600195]: An error of vascular morphogenesis characterized by dilated, serpiginous channels. {ECO:0000269|PubMed:10369874, ECO:0000269|PubMed:19079259, ECO:0000269|PubMed:19888299, ECO:0000269|PubMed:8980225}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Somatic mutations of TEK are associated with solitary and multiple sporadic venous malformations. {ECO:0000269|PubMed:19079259}.; DISEASE: Note=May play a role in a range of diseases with a vascular component, including neovascularization of tumors, psoriasis and inflammation.; DISEASE: Glaucoma 3, primary congenital, E (GLC3E) [MIM:617272]: An autosomal dominant form of primary congenital glaucoma (PCG). PCG is characterized by marked increase of intraocular pressure at birth or early childhood, large ocular globes (buphthalmos) and corneal edema. It results from developmental defects of the trabecular meshwork and anterior chamber angle of the eye that prevent adequate drainage of aqueous humor. {ECO:0000269|PubMed:27270174}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);HIF-1 signaling pathway - Homo sapiens (human);Rap1 signaling pathway - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Rheumatoid arthritis - Homo sapiens (human);Angiogenesis;Angiogenesis overview;Rac1-Pak1-p38-MMP-2 pathway;Wnt Signaling Pathway;Focal Adhesion-PI3K-Akt-mTOR-signaling pathway;PI3K-Akt Signaling Pathway;Ras Signaling;Signal Transduction;SHP2 signaling;Tie2 Signaling;Cell surface interactions at the vascular wall;Hemostasis;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Angiopoietin receptor Tie2-mediated signaling (Consensus)

Recessive Scores

• pRec: 0.102

Intolerance Scores

• loftool: 0.0457
• rvis_EVS: -0.33
• rvis_percentile_EVS: 30.9

Haploinsufficiency Scores

• pHI: 0.900
• hipred: Y
• hipred_score: 0.853
• ghis: 0.563

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.735

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Tek
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; normal 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); hematopoietic system 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); embryo phenotype; homeostasis/metabolism phenotype; muscle phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: tek
• Affected structure: subintestinal vein
• Phenotype tag: abnormal
• Phenotype quality: morphology

Gene ontology

• Biological process: MAPK cascade;angiogenesis;response to hypoxia;positive regulation of protein phosphorylation;endothelial cell proliferation;positive regulation of endothelial cell proliferation;endochondral ossification;sprouting angiogenesis;signal transduction;transmembrane receptor protein tyrosine kinase signaling pathway;cell-cell signaling;heart development;positive regulation of endothelial cell migration;positive regulation of phosphatidylinositol 3-kinase signaling;negative regulation of angiogenesis;peptidyl-tyrosine phosphorylation;regulation of establishment or maintenance of cell polarity;substrate adhesion-dependent cell spreading;negative regulation of apoptotic process;regulation of vascular permeability;response to peptide hormone;positive regulation of phosphatidylinositol 3-kinase activity;response to estrogen;positive regulation of angiogenesis;protein autophosphorylation;Tie signaling pathway;negative regulation of inflammatory response;leukocyte migration;protein complex oligomerization;response to cAMP;positive regulation of focal adhesion assembly;positive regulation of protein kinase B signaling;definitive hemopoiesis;heart trabecula formation;positive regulation of ERK1 and ERK2 cascade;glomerulus vasculature development;positive regulation of intracellular signal transduction;positive regulation of actin cytoskeleton reorganization;regulation of endothelial cell apoptotic process;negative regulation of endothelial cell apoptotic process
• Cellular component: stress fiber;extracellular region;microtubule organizing center;actin filament;plasma membrane;integral component of plasma membrane;microvillus;cell-cell junction;focal adhesion;basal plasma membrane;cell surface;basolateral plasma membrane;apical plasma membrane;receptor complex;membrane raft
• Molecular function: protein kinase activity;protein tyrosine kinase activity;transmembrane receptor protein tyrosine kinase activity;Ras guanyl-nucleotide exchange factor activity;protein binding;ATP binding;growth factor binding;signaling receptor activity