9-27197488-G-T

Position:

chr9-27197488-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000459.5(TEK):c.1798G>T(p.Val600Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.046 in 1,613,970 control chromosomes in the GnomAD database, including 1,925 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 129 hom., cov: 31)

Exomes 𝑓: 0.047 ( 1796 hom. )

Consequence

TEK
NM_000459.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 1.28

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0022735).

BP6

Variant 9-27197488-G-T is Benign according to our data. Variant chr9-27197488-G-T is described in ClinVar as [Benign]. Clinvar id is 366430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-27197488-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.056 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TEK	NM_000459.5 linkuse as main transcript	c.1798G>T	p.Val600Leu	missense_variant	12/23	ENST00000380036.10	NP_000450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TEK	ENST00000380036.10 linkuse as main transcript	c.1798G>T	p.Val600Leu	missense_variant	12/23	1	NM_000459.5	ENSP00000369375.4		Q02763-1

Frequencies

GnomAD3 genomes

AF:

0.0352

AC:

5356

AN:

152020

Hom.:

129

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00920

Gnomad AMI

AF:

0.0824

Gnomad AMR

AF:

0.0369

Gnomad ASJ

AF:

0.0991

Gnomad EAS

AF:

0.0465

Gnomad SAS

AF:

0.0623

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0471

Gnomad OTH

AF:

0.0422

GnomAD3 exomes

AF:

0.0458

AC:

11495

AN:

251234

Hom.:

313

AF XY:

0.0480

AC XY:

6522

AN XY:

135758

show subpopulations

Gnomad AFR exome

AF:

0.00923

Gnomad AMR exome

AF:

0.0346

Gnomad ASJ exome

AF:

0.0942

Gnomad EAS exome

AF:

0.0558

Gnomad SAS exome

AF:

0.0638

Gnomad FIN exome

AF:

0.0156

Gnomad NFE exome

AF:

0.0490

Gnomad OTH exome

AF:

0.0517

GnomAD4 exome

AF:

0.0471

AC:

68878

AN:

1461834

Hom.:

1796

Cov.:

AF XY:

0.0481

AC XY:

34950

AN XY:

727212

show subpopulations

Gnomad4 AFR exome

AF:

0.00696

Gnomad4 AMR exome

AF:

0.0358

Gnomad4 ASJ exome

AF:

0.0957

Gnomad4 EAS exome

AF:

0.0421

Gnomad4 SAS exome

AF:

0.0632

Gnomad4 FIN exome

AF:

0.0178

Gnomad4 NFE exome

AF:

0.0477

Gnomad4 OTH exome

AF:

0.0496

GnomAD4 genome

AF:

0.0352

AC:

5354

AN:

152136

Hom.:

129

Cov.:

AF XY:

0.0345

AC XY:

2562

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00918

Gnomad4 AMR

AF:

0.0368

Gnomad4 ASJ

AF:

0.0991

Gnomad4 EAS

AF:

0.0466

Gnomad4 SAS

AF:

0.0617

Gnomad4 FIN

AF:

0.0139

Gnomad4 NFE

AF:

0.0471

Gnomad4 OTH

AF:

0.0417

Alfa

AF:

0.0434

Hom.:

138

Bravo

AF:

0.0357

TwinsUK

AF:

0.0467

AC:

173

ALSPAC

AF:

0.0511

AC:

197

ESP6500AA

AF:

0.0111

AC:

ESP6500EA

AF:

0.0483

AC:

415

ExAC

AF:

0.0455

AC:

5523

Asia WGS

AF:

0.0350

AC:

122

AN:

3478

EpiCase

AF:

0.0515

EpiControl

AF:

0.0542

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -

Multiple cutaneous and mucosal venous malformations

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.42

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.24

.;T;.;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.85

T;T;T;T

MetaRNN

Benign

0.0023

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

.;N;.;.

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.66

N;N;N;N

REVEL

Benign

0.058

Sift

Benign

0.26

T;T;T;T

Sift4G

Benign

0.68

T;T;T;T

Polyphen

0.0010

.;B;.;.

Vest4

0.17

MutPred

0.64

.;Gain of sheet (P = 0.0827);.;.;

MPC

0.21

ClinPred

0.0041

GERP RS

4.6

Varity_R

0.12

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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