TIE1

protein-coding

tyrosine kinase with immunoglobulin like and EGF like domains 1, the group of Fibronectin type III domain containing|Immunoglobulin like domain containing|Receptor tyrosine kinases

Gene summary

This gene encodes a member of the tyrosine protein kinase family. The encoded protein plays a critical role in angiogenesis and blood vessel stability by inhibiting angiopoietin 1 signaling through the endothelial receptor tyrosine kinase Tie2. Ectodomain cleavage of the encoded protein relieves inhibition of Tie2 and is mediated by multiple factors including vascular endothelial growth factor. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

Previous symbols:

MANE transcript

NM_005424.5

Inheritance

ClinVar variants

P:2U:183B:12

Top phenotype

lymphatic malformation 11

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr1:43,300,982-43,323,108

External References & Databases

Ensembl (ENSG00000066056)

Transcript & Mutation Effects

hg38 • Region Span ~22.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

lymphatic malformation 11LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0030316

Submitter: Ambry Genetics

lymphatic malformation 11LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0030316

Submitter: Labcorp Genetics (formerly Invitae)

lymphatic malformation 11STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030316

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TIE1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 168

not providedTotal: 14

Lymphatic malformation 11Total: 3

TIE1-related disorderTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005424.5. 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				4 clinvar	4 clinvar	8
missense	2 clinvar		171 clinvar	4 clinvar		177
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			10 clinvar			10
Total	2	0	183	8	4	197

Highest pathogenic variant AF is 0.0008263388

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005424.5	RefSeq	NP_005415.1	23	MANE Select
ENST00000372476.8	Ensembl	ENSP00000361554.3	23	MANE Select
NM_001253357.2	RefSeq	NP_001240286.1	23	Standard
ENST00000714825.1	Ensembl	ENSP00000520026.1	3	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
tie1	Danio rerio	Structure: blood vessel endothelium Quality: mislocalised abnormal

Gene / Model

Organism

Observed Phenotype

tie1

Danio rerio

Structure: blood vessel endothelium

Quality: mislocalised

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Rac1-Pak1-p38-MMP-2 pathway

Biological Process

angiogenesis
vasculogenesis
in utero embryonic development
signal transduction
transmembrane receptor protein tyrosine kinase signaling pathway

Molecular Function

transmembrane receptor protein tyrosine kinase activity
protein binding
ATP binding

Cellular Component

integral component of plasma membrane
receptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372476
Coding exons: 23
Length: 22116
Individuals with no LoFs: 125643
Homozygous LoFs: 0
Heterozygous LoFs: 105
Defined: 125748
p: 0.000418

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.51	615	730	0.843	0.0000499	7249
Missense (PolyPhen)		259	331.27	0.78183		3396
Synonymous	1.53	263	296	0.887	0.0000197	2398
Loss of Function	2.27	39	57.6	0.677	0.00000302	611

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00044	0.00043	rare
Latino/Admixed American	0.00050	0.00049	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00027	0.00027	rare
Finnish	0.00025	0.00014	rare
European (Non-Finnish)	0.00044	0.00043	rare
South Asian	0.00067	0.00065	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transmembrane tyrosine-protein kinase that may modulate TEK/TIE2 activity and contribute to the regulation of angiogenesis. {ECO:0000269|PubMed:20227369}.;

Recessive Scores

pRec: 0.268

Intolerance Scores

LoFtool: 0.870
RVIS EVS: -1.97
RVIS percentile EVS: 1.83

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.677

Gene Damage Prediction

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