rs1334811

Variant names:

• chr9-27190657-G-A
• rs1334811
• NM_000459.5:c.1456G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.39
• Publications: 24 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 366425.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.12 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEK	NM_000459.5	c.1456G>A	p.Val486Ile	missense_variant	Exon 10 of 23	ENST00000380036.10	NP_000450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEK	ENST00000380036.10	c.1456G>A	p.Val486Ile	missense_variant	Exon 10 of 23	1	NM_000459.5	ENSP00000369375.4

Frequencies

GnomAD3 genomes AF: 0.0656 AC: 9976 AN: 152084 Hom.: 460 Cov.: 32

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

GnomAD2 exomes AF: 0.0534 AC: 13407 AN: 250992 AF XY: 0.0569

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 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.: 32 AF XY: 0.0486 AC XY: 35305 AN XY: 727132

African (AFR) AF: 0.134 AC: 4485 AN: 33456

American (AMR) AF: 0.0331 AC: 1481 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0650 AC: 1698 AN: 26122

East Asian (EAS) AF: 0.0194 AC: 771 AN: 39694

South Asian (SAS) AF: 0.121 AC: 10455 AN: 86254

European-Finnish (FIN) AF: 0.0206 AC: 1099 AN: 53414

Middle Eastern (MID) AF: 0.103 AC: 596 AN: 5764

European-Non Finnish (NFE) AF: 0.0393 AC: 43750 AN: 1111838

Other (OTH) AF: 0.0542 AC: 3270 AN: 60382

GnomAD4 genome AF: 0.0658 AC: 10013 AN: 152202 Hom.: 468 Cov.: 32 AF XY: 0.0657 AC XY: 4894 AN XY: 74434

African (AFR) AF: 0.123 AC: 5103 AN: 41510

American (AMR) AF: 0.0477 AC: 730 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0619 AC: 215 AN: 3472

East Asian (EAS) AF: 0.0116 AC: 60 AN: 5186

South Asian (SAS) AF: 0.128 AC: 617 AN: 4824

European-Finnish (FIN) AF: 0.0197 AC: 209 AN: 10608

Middle Eastern (MID) AF: 0.126 AC: 37 AN: 294

European-Non Finnish (NFE) AF: 0.0421 AC: 2865 AN: 67988

Other (OTH) AF: 0.0724 AC: 153 AN: 2112

Alfa AF: 0.0546 Hom.: 946

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

Submissions by phenotype

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Nov 29, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

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

- -

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.015	.;T;T;.;.
Eigen	Benign	0.019
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
MetaRNN	Benign	0.0023	T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.1	.;.;L;.;.
PhyloP100		3.4
PrimateAI	Benign	0.41	T
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	T
GERP RS		4.7
Varity_R		0.11
gMVP		0.25
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1334811; hg19: chr9-27190655;