9-27197488-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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

Publications

26 publications found

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 Gene-Disease associations (from GenCC):

multiple cutaneous and mucosal venous malformations
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
primary congenital glaucoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
TEK-related primary glaucoma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
glaucoma 3, primary congenital, E
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
congenital glaucoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TEK links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 366430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000459.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TEK	NM_000459.5	MANE Select	c.1798G>T	p.Val600Leu	missense	Exon 12 of 23	NP_000450.3
TEK	NM_001375475.1		c.1798G>T	p.Val600Leu	missense	Exon 12 of 23	NP_001362404.1
TEK	NM_001290077.2		c.1669G>T	p.Val557Leu	missense	Exon 11 of 22	NP_001277006.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TEK	ENST00000380036.10	TSL:1 MANE Select	c.1798G>T	p.Val600Leu	missense	Exon 12 of 23	ENSP00000369375.4
TEK	ENST00000519080.1	TSL:1	c.1228G>T	p.Val410Leu	missense	Exon 9 of 10	ENSP00000428337.1
TEK	ENST00000406359.8	TSL:2	c.1669G>T	p.Val557Leu	missense	Exon 11 of 22	ENSP00000383977.4

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

GnomAD2 exomes

AF:

0.0458

AC:

11495

AN:

251234

AF XY:

0.0480

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 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

African (AFR)

AF:

0.00696

AC:

233

AN:

33480

American (AMR)

AF:

0.0358

AC:

1601

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0957

AC:

2502

AN:

26136

East Asian (EAS)

AF:

0.0421

AC:

1670

AN:

39690

South Asian (SAS)

AF:

0.0632

AC:

5448

AN:

86258

European-Finnish (FIN)

AF:

0.0178

AC:

949

AN:

53420

Middle Eastern (MID)

AF:

0.0808

AC:

466

AN:

5768

European-Non Finnish (NFE)

AF:

0.0477

AC:

53011

AN:

1111970

Other (OTH)

AF:

0.0496

AC:

2998

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

4270

8540

12810

17080

21350

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1946

3892

5838

7784

9730

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0352

AC:

5354

AN:

152136

Hom.:

129

Cov.:

AF XY:

0.0345

AC XY:

2562

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00918

AC:

381

AN:

41514

American (AMR)

AF:

0.0368

AC:

563

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0991

AC:

344

AN:

3470

East Asian (EAS)

AF:

0.0466

AC:

241

AN:

5168

South Asian (SAS)

AF:

0.0617

AC:

297

AN:

4810

European-Finnish (FIN)

AF:

0.0139

AC:

147

AN:

10598

Middle Eastern (MID)

AF:

0.0578

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0471

AC:

3201

AN:

67980

Other (OTH)

AF:

0.0417

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

253

505

758

1010

1263

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

216

288

360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0438

Hom.:

455

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

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

May 05, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Multiple cutaneous and mucosal venous malformations

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.24

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.24

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.85

MetaRNN

Benign

0.0023

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PhyloP100

1.3

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.66

REVEL

Benign

0.058

Sift

Benign

0.26

Sift4G

Benign

0.68

Polyphen

0.0010

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

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over