rs80338909

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate

The NM_000459.5(TEK):c.2690A>C(p.Tyr897Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y897C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

TEK
NM_000459.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:2O:1

Conservation

PhyloP100: 9.29

Variant links:

Genes affected

TEK (HGNC:11724): (TEK receptor tyrosine kinase) This gene encodes a receptor that belongs to the protein tyrosine kinase Tie2 family. The encoded protein possesses a unique extracellular region that contains two immunoglobulin-like domains, three epidermal growth factor (EGF)-like domains and three fibronectin type III repeats. The ligand angiopoietin-1 binds to this receptor and mediates a signaling pathway that functions in embryonic vascular development. Mutations in this gene are associated with inherited venous malformations of the skin and mucous membranes. Alternative splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Feb 2014]

TEK links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a strand (size 6) in uniprot entity TIE2_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000459.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-27212710-A-G is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.963

PP5

Variant 9-27212710-A-C is Pathogenic according to our data. Variant chr9-27212710-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 9294.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-27212710-A-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEK	NM_000459.5 link	c.2690A>C	p.Tyr897Ser	missense_variant	Exon 17 of 23	ENST00000380036.10	NP_000450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TEK	ENST00000380036.10 link	c.2690A>C	p.Tyr897Ser	missense_variant	Exon 17 of 23	1	NM_000459.5	ENSP00000369375.4	Q02763-1
TEK	ENST00000406359.8 link	c.2561A>C	p.Tyr854Ser	missense_variant	Exon 16 of 22	2		ENSP00000383977.4	Q02763-2
TEK	ENST00000519097.5 link	c.2246A>C	p.Tyr749Ser	missense_variant	Exon 15 of 21	2		ENSP00000430686.1	Q02763-3
TEK	ENST00000615002.4 link	c.*1191A>C		3_prime_UTR_variant	Exon 17 of 23	5		ENSP00000480251.1	B5A954

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Multiple cutaneous and mucosal venous malformations

Pathogenic:1Other:1

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Blue rubber bleb nevus

Pathogenic:1

May 11, 2021

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been previously reported in individuals with venous malformations and blue rubber bleb nevus syndrome (PMID: 33105631, PMID: 19079259, PMID: 27519652). This variant has been previously reported in a family with heritable cutaneomucosal venous malformation (PMID: 10369874, NBK1967). This variant is absent from large population studies (gnomAD v2.1.1), and computational algorithms predict a deleterious effect on protein function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

.;D;.

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Uncertain

0.11

MutationAssessor

Benign

0.27

.;N;.

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.1

D;D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.019

D;D;D

Sift4G

Benign

0.083

T;T;D

Polyphen

1.0

.;D;.

Vest4

0.93

MutPred

0.85

.;Loss of sheet (P = 0.0817);.;

MVP

0.95

MPC

2.5

ClinPred

0.99

GERP RS

5.6

Varity_R

0.76

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over