NM_000459.5:c.2690A>C

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• 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 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	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	Appris	UniProt
TEK	ENST00000380036.10	c.2690A>C	p.Tyr897Ser	missense_variant	Exon 17 of 23	1	NM_000459.5	ENSP00000369375.4
TEK	ENST00000406359.8	c.2561A>C	p.Tyr854Ser	missense_variant	Exon 16 of 22	2		ENSP00000383977.4
TEK	ENST00000519097.5	c.2246A>C	p.Tyr749Ser	missense_variant	Exon 15 of 21	2		ENSP00000430686.1
TEK	ENST00000615002.4	c.*1191A>C		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: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Multiple cutaneous and mucosal venous malformations Pathogenic:1 Other: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	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	.;D;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	0.27	.;N;.
PrimateAI	Pathogenic	0.89	D
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	D
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

Other links and lift over

dbSNP: rs80338909; hg19: chr9-27212708;