chr9-27109640-C-G

Position:

chr9-27109640-C-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_000459.5(TEK):c.50C>G(p.Ser17Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000539 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00030 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

TEK
NM_000459.5 missense, splice_region

Scores

Splicing: ADA: 0.004299

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.57

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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.099089384).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000302 (46/152238) while in subpopulation AFR AF= 0.00106 (44/41544). AF 95% confidence interval is 0.00081. There are 0 homozygotes in gnomad4. There are 23 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 46 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TEK	NM_000459.5 linkuse as main transcript	c.50C>G	p.Ser17Cys	missense_variant, splice_region_variant	1/23	ENST00000380036.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TEK	ENST00000380036.10 linkuse as main transcript	c.50C>G	p.Ser17Cys	missense_variant, splice_region_variant	1/23	1	NM_000459.5	P1	Q02763-1

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00101

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251200

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135788

show subpopulations

Gnomad AFR exome

AF:

0.000861

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

727228

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.000302

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.000336

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.50C>G (p.S17C) alteration is located in exon 1 (coding exon 1) of the TEK gene. This alteration results from a C to G substitution at nucleotide position 50, causing the serine (S) at amino acid position 17 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.18

CADD

Uncertain

DANN

Benign

0.89

DEOGEN2

Benign

0.030

.;T;T;.;.

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.40

T;T;T;T;T

M_CAP

Benign

0.026

MetaRNN

Benign

0.091

T;T;T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Benign

0.55

N;.;N;N;.

MutationTaster

Benign

0.82

N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-1.6

N;.;N;N;N

REVEL

Benign

0.14

Sift

Uncertain

0.017

D;.;D;D;D

Sift4G

Uncertain

0.049

D;T;T;T;D

Polyphen

0.81

.;.;P;.;P

Vest4

0.43

MVP

0.65

MPC

0.20

ClinPred

0.059

GERP RS

4.6

Varity_R

0.12

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0043

dbscSNV1_RF

Benign

0.17

SpliceAI score (max)

0.11

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