rs1334811

Positions:

chr9-27190657-G-A

Variant summary

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

The NM_000459.5(TEK):c.1456G>A(p.Val486Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0481 in 1,613,842 control chromosomes in the GnomAD database, including 2,771 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 0.066 ( 468 hom., cov: 32)

Exomes 𝑓: 0.046 ( 2303 hom. )

Consequence

TEK
NM_000459.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.39

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=0.0022887588).

BP6

Variant 9-27190657-G-A is Benign according to our data. Variant chr9-27190657-G-A is described in ClinVar as [Benign]. Clinvar id is 366425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-27190657-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.12 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.1456G>A	p.Val486Ile	missense_variant	10/23	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.1456G>A	p.Val486Ile	missense_variant	10/23	1	NM_000459.5	ENSP00000369375	P1	Q02763-1

Frequencies

GnomAD3 genomes

AF:

0.0656

AC:

9976

AN:

152084

Hom.:

460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.122

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.0478

Gnomad ASJ

AF:

0.0619

Gnomad EAS

AF:

0.0115

Gnomad SAS

AF:

0.128

Gnomad FIN

AF:

0.0197

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0421

Gnomad OTH

AF:

0.0737

GnomAD3 exomes

AF:

0.0534

AC:

13407

AN:

250992

Hom.:

589

AF XY:

0.0569

AC XY:

7710

AN XY:

135596

show subpopulations

Gnomad AFR exome

AF:

0.122

Gnomad AMR exome

AF:

0.0305

Gnomad ASJ exome

AF:

0.0651

Gnomad EAS exome

AF:

0.00381

Gnomad SAS exome

AF:

0.125

Gnomad FIN exome

AF:

0.0198

Gnomad NFE exome

AF:

0.0446

Gnomad OTH exome

AF:

0.0567

GnomAD4 exome

AF:

0.0463

AC:

67605

AN:

1461640

Hom.:

2303

Cov.:

AF XY:

0.0486

AC XY:

35305

AN XY:

727132

show subpopulations

Gnomad4 AFR exome

AF:

0.134

Gnomad4 AMR exome

AF:

0.0331

Gnomad4 ASJ exome

AF:

0.0650

Gnomad4 EAS exome

AF:

0.0194

Gnomad4 SAS exome

AF:

0.121

Gnomad4 FIN exome

AF:

0.0206

Gnomad4 NFE exome

AF:

0.0393

Gnomad4 OTH exome

AF:

0.0542

GnomAD4 genome

AF:

0.0658

AC:

10013

AN:

152202

Hom.:

468

Cov.:

AF XY:

0.0657

AC XY:

4894

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.123

Gnomad4 AMR

AF:

0.0477

Gnomad4 ASJ

AF:

0.0619

Gnomad4 EAS

AF:

0.0116

Gnomad4 SAS

AF:

0.128

Gnomad4 FIN

AF:

0.0197

Gnomad4 NFE

AF:

0.0421

Gnomad4 OTH

AF:

0.0724

Alfa

AF:

0.0518

Hom.:

616

Bravo

AF:

0.0686

TwinsUK

AF:

0.0415

AC:

154

ALSPAC

AF:

0.0348

AC:

134

ESP6500AA

AF:

0.126

AC:

553

ESP6500EA

AF:

0.0491

AC:

422

ExAC

AF:

0.0574

AC:

6964

Asia WGS

AF:

0.0770

AC:

269

AN:

3478

EpiCase

AF:

0.0549

EpiControl

AF:

0.0535

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -

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

0.073

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.015

.;T;T;.;.

Eigen

Benign

0.019

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.88

D;D;D;D;D

MetaRNN

Benign

0.0023

T;T;T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.1

.;.;L;.;.

MutationTaster

Benign

1.0

N;N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.59

N;.;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.18

T;.;T;T;T

Sift4G

Benign

0.17

T;T;T;T;T

Polyphen

0.42

.;.;B;.;.

Vest4

0.16

MPC

0.28

ClinPred

0.0048

GERP RS

4.7

Varity_R

0.11

gMVP

0.25

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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