rs638203

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 518397.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-27203136-A-G is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
TEK	NM_000459.5	c.2209+17A>G		intron_variant		ENST00000380036.10	NP_000450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TEK	ENST00000380036.10	c.2209+17A>G		intron_variant		1	NM_000459.5	ENSP00000369375	P1
TEK	ENST00000406359.8	c.2080+17A>G		intron_variant		2		ENSP00000383977
TEK	ENST00000519097.5	c.1768+17A>G		intron_variant		2		ENSP00000430686
TEK	ENST00000615002.4	c.*710+17A>G		intron_variant		5		ENSP00000480251

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

GnomAD3 exomes AF: 0.471 AC: 117403 AN: 249446 Hom.: 28509 AF XY: 0.465 AC XY: 62803 AN XY: 134938

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 SAS exome AF: 0.382

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

Gnomad4 AFR exome AF: 0.362

Gnomad4 AMR exome AF: 0.523

Gnomad4 ASJ exome AF: 0.390

Gnomad4 EAS exome AF: 0.384

Gnomad4 SAS exome AF: 0.380

Gnomad4 FIN exome AF: 0.622

Gnomad4 NFE exome AF: 0.486

Gnomad4 OTH exome AF: 0.465

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

Gnomad4 AFR AF: 0.368

Gnomad4 AMR AF: 0.486

Gnomad4 ASJ AF: 0.372

Gnomad4 EAS AF: 0.400

Gnomad4 SAS AF: 0.379

Gnomad4 FIN AF: 0.642

Gnomad4 NFE AF: 0.490

Gnomad4 OTH AF: 0.429

Alfa AF: 0.458 Hom.: 22586

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Multiple cutaneous and mucosal venous malformations Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Glaucoma 3, primary congenital, E Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 10, 2021

- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.5
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs638203; hg19: chr9-27203134; COSMIC: COSV66227350; COSMIC: COSV66227350;