rs638203

Variant names:

• chr9-27203136-A-G
• rs638203
• NM_000459.5:c.2209+17A>G

Your query was ambiguous. Multiple possible variants found:

• chr9-27203136-A-G
• chr9-27203136-A-T

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.2209+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,612,434 control chromosomes in the GnomAD database, including 185,157 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16329 hom., cov: 32)
  • Exomes 𝑓: 0.48 (168828 hom.)
• Consequence: TEK NM_000459.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.408
• Publications: 23 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 (BayesDel_noAF=-0.86).
• BP6: Variant 9-27203136-A-G is Benign according to our data. Variant chr9-27203136-A-G is described in ClinVar as Benign. ClinVar VariationId is 518397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEK	NM_000459.5	c.2209+17A>G		intron_variant	Intron 13 of 22	ENST00000380036.10	NP_000450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEK	ENST00000380036.10	c.2209+17A>G		intron_variant	Intron 13 of 22	1	NM_000459.5	ENSP00000369375.4
TEK	ENST00000406359.8	c.2080+17A>G		intron_variant	Intron 12 of 21	2		ENSP00000383977.4
TEK	ENST00000519097.5	c.1768+17A>G		intron_variant	Intron 11 of 20	2		ENSP00000430686.1
TEK	ENST00000615002.4	c.*710+17A>G		intron_variant	Intron 13 of 22	5		ENSP00000480251.1

Frequencies

GnomAD3 genomes AF: 0.457 AC: 69376 AN: 151894 Hom.: 16323 Cov.: 32

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.400

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.395

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.433

GnomAD2 exomes AF: 0.471 AC: 117403 AN: 249446 AF XY: 0.465

Gnomad AFR exome AF: 0.364

Gnomad AMR exome AF: 0.532

Gnomad ASJ exome AF: 0.386

Gnomad EAS exome AF: 0.392

Gnomad FIN exome AF: 0.627

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.469

GnomAD4 exome AF: 0.477 AC: 697296 AN: 1460422 Hom.: 168828 Cov.: 37 AF XY: 0.474 AC XY: 344755 AN XY: 726584

African (AFR) AF: 0.362 AC: 12092 AN: 33438

American (AMR) AF: 0.523 AC: 23342 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 10199 AN: 26122

East Asian (EAS) AF: 0.384 AC: 15220 AN: 39676

South Asian (SAS) AF: 0.380 AC: 32728 AN: 86226

European-Finnish (FIN) AF: 0.622 AC: 33225 AN: 53380

Middle Eastern (MID) AF: 0.391 AC: 2252 AN: 5764

European-Non Finnish (NFE) AF: 0.486 AC: 540176 AN: 1110816

Other (OTH) AF: 0.465 AC: 28062 AN: 60350

GnomAD4 genome AF: 0.456 AC: 69392 AN: 152012 Hom.: 16329 Cov.: 32 AF XY: 0.462 AC XY: 34371 AN XY: 74326

African (AFR) AF: 0.368 AC: 15266 AN: 41464

American (AMR) AF: 0.486 AC: 7407 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1290 AN: 3466

East Asian (EAS) AF: 0.400 AC: 2071 AN: 5172

South Asian (SAS) AF: 0.379 AC: 1826 AN: 4822

European-Finnish (FIN) AF: 0.642 AC: 6778 AN: 10564

Middle Eastern (MID) AF: 0.377 AC: 110 AN: 292

European-Non Finnish (NFE) AF: 0.490 AC: 33282 AN: 67964

Other (OTH) AF: 0.429 AC: 906 AN: 2110

Alfa AF: 0.458 Hom.: 31102

Bravo AF: 0.443

Asia WGS AF: 0.424 AC: 1476 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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:2

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Glaucoma 3, primary congenital, E Benign:1

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.5
DANN	Benign	0.75
PhyloP100		-0.41
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs638203; hg19: chr9-27203134; COSMIC: COSV66227350; COSMIC: COSV66227350;