rs581724

Variant names:

• chr9-27187424-G-T
• rs581724
• NM_000459.5:c.1327+1795G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000459.5(TEK):​c.1327+1795G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 151,986 control chromosomes in the GnomAD database, including 15,631 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.45 (15631 hom., cov: 33)
• Consequence: TEK NM_000459.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.118
• Publications: 15 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.99).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEK	NM_000459.5	c.1327+1795G>T		intron_variant	Intron 9 of 22	ENST00000380036.10	NP_000450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEK	ENST00000380036.10	c.1327+1795G>T		intron_variant	Intron 9 of 22	1	NM_000459.5	ENSP00000369375.4

Frequencies

GnomAD3 genomes AF: 0.447 AC: 67854 AN: 151866 Hom.: 15602 Cov.: 33

Gnomad AFR AF: 0.448

Gnomad AMI AF: 0.518

Gnomad AMR AF: 0.531

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.491

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.452

Gnomad NFE AF: 0.442

Gnomad OTH AF: 0.460

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.447 AC: 67935 AN: 151986 Hom.: 15631 Cov.: 33 AF XY: 0.449 AC XY: 33370 AN XY: 74292

African (AFR) AF: 0.448 AC: 18582 AN: 41432

American (AMR) AF: 0.531 AC: 8109 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1529 AN: 3470

East Asian (EAS) AF: 0.117 AC: 605 AN: 5190

South Asian (SAS) AF: 0.493 AC: 2369 AN: 4810

European-Finnish (FIN) AF: 0.485 AC: 5111 AN: 10546

Middle Eastern (MID) AF: 0.455 AC: 132 AN: 290

European-Non Finnish (NFE) AF: 0.442 AC: 30054 AN: 67956

Other (OTH) AF: 0.460 AC: 972 AN: 2114

Alfa AF: 0.451 Hom.: 26579

Bravo AF: 0.452

Asia WGS AF: 0.334 AC: 1166 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.0
DANN	Benign	0.31
PhyloP100		-0.12
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs581724; hg19: chr9-27187422; COSMIC: COSV66228247;