9-27212710-A-G

Variant names:

• chr9-27212710-A-G
• rs80338909
• NM_000459.5:c.2690A>G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000459.5(TEK):​c.2690A>G​(p.Tyr897Cys) 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y897F) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TEK NM_000459.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 9.29

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.959
• PP5: Variant 9-27212710-A-G is Pathogenic according to our data. Variant chr9-27212710-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 30053.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-27212710-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEK	NM_000459.5	c.2690A>G	p.Tyr897Cys	missense_variant	Exon 17 of 23	ENST00000380036.10	NP_000450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEK	ENST00000380036.10	c.2690A>G	p.Tyr897Cys	missense_variant	Exon 17 of 23	1	NM_000459.5	ENSP00000369375.4
TEK	ENST00000406359.8	c.2561A>G	p.Tyr854Cys	missense_variant	Exon 16 of 22	2		ENSP00000383977.4
TEK	ENST00000519097.5	c.2246A>G	p.Tyr749Cys	missense_variant	Exon 15 of 21	2		ENSP00000430686.1
TEK	ENST00000615002.4	c.*1191A>G		3_prime_UTR_variant	Exon 17 of 23	5		ENSP00000480251.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Multiple cutaneous and mucosal venous malformations Pathogenic:2

Oct 12, 2023

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TEK c.2690A>G (p.Tyr897Cys) variant was identified at an allelic fraction consistent with somatic origin. This variant has been reported in multiple individuals affected with vascular malformations (Ten Broek RW et al., PMID: 30677207; Soblet J et al., PMID: 23801934; Wouters V et al., PMID: 19888299; Limaye N et al., PMID: 19079259; Zhou M et al., PMID: 26115772; Ye C et al., PMID: 21962923) and Blue Rubber Bleb Nevus (BRBN) Syndrome (Soblet J et al., PMID: 27519652). This variant has been reported in the ClinVar database as a pathogenic variant (ClinVar ID: 30053). This variant is absent from the general population (gnomAD v.3.1.2), indicating that it is not a common variant. The TEK c.2690A>G (p.Tyr897Cys) variant resides within the cytoplasmic kinase domain of TEK, which is a critical functional domain (Shewchuk LM et al., PMID: 11080633). Functional studies show that this variant increases ligand-independent receptor phosphorylation as compared with the wild-type receptor, an effect that is compounded in the presence of double variants (Limaye N et al., PMID: 19079259, Nätynki M et al., PMID: 26319232; Wouters V et al., PMID: 19888299). Computational predictors indicate that the variant is damaging, evidence that correlates with impact on TEK function. Based on an internally-developed protocol informed by the ACMG/AMP guidelines (Richards S et al., PMID: 25741868), the TEK c.2690A>G (p.Tyr897Cys) variant is classified as pathogenic. -

Apr 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Oct 02, 2017

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Tyr897Cys variant has been previously reported in association with vascular malformations in 3 individuals from 3 generations (Wouters 2010). Another change of the same amino acid, Tyr897Ser has been identified in 6 individuals with vascular malformations from three generations (Calvert 1999). Furthermore, in vitro functional studies performed by Wouters et al. demonstrated that the p.Tyr897Cys change greatly increases ligand independent phosphorylation in a manner similar to other pathogenic variants. It is absent from general population databases such as 1000 Genomes, NHLBI GO Exome Sequencing Project (ESP), and the genome Aggregation Database (gnomAD) browser. Based on these observations the p.Tyr897Cys variant has been classified pathogenic. -

Abnormal cardiovascular system morphology Pathogenic:1

-

MAGI's Lab - Research, MAGI Group

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

- -

Ventricular septal defect;C0346072:Blue rubber bleb nevus Pathogenic:1

Apr 17, 2025

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG criteria applied: PS3_supporting, PS4, PM1, PM2, PP1, PP3, and PP4_strong -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	.;D;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.76	.;N;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.015	D;D;D
Sift4G	Uncertain	0.043	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.89
MutPred		0.85		.;Gain of catalytic residue at L898 (P = 0.0236);.;
MVP		0.97
MPC		2.4
ClinPred		0.99	D
GERP RS		5.6
Varity_R		0.68
gMVP		0.90

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

Other links and lift over

dbSNP: rs80338909; hg19: chr9-27212708;