rs633903

Variant names:

• chr9-27196121-T-G
• rs633903
• NM_000459.5:c.1625-1194T>G

Variant summary

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

The NM_000459.5(TEK):​c.1625-1194T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.199 in 152,194 control chromosomes in the GnomAD database, including 3,426 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 0.20 (3426 hom., cov: 32)
• Consequence: TEK NM_000459.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.232
• Publications: 13 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=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEK	NM_000459.5	c.1625-1194T>G		intron_variant	Intron 11 of 22	ENST00000380036.10	NP_000450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEK	ENST00000380036.10	c.1625-1194T>G		intron_variant	Intron 11 of 22	1	NM_000459.5	ENSP00000369375.4

Frequencies

GnomAD3 genomes AF: 0.199 AC: 30239 AN: 152076 Hom.: 3428 Cov.: 32

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.148

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.178

Gnomad FIN AF: 0.328

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.185

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

GnomAD4 genome AF: 0.199 AC: 30240 AN: 152194 Hom.: 3426 Cov.: 32 AF XY: 0.200 AC XY: 14850 AN XY: 74392

African (AFR) AF: 0.109 AC: 4521 AN: 41552

American (AMR) AF: 0.147 AC: 2256 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.165 AC: 572 AN: 3472

East Asian (EAS) AF: 0.117 AC: 607 AN: 5178

South Asian (SAS) AF: 0.178 AC: 859 AN: 4824

European-Finnish (FIN) AF: 0.328 AC: 3472 AN: 10582

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.253 AC: 17221 AN: 67966

Other (OTH) AF: 0.184 AC: 388 AN: 2114

Alfa AF: 0.222 Hom.: 2868

Bravo AF: 0.182

Asia WGS AF: 0.151 AC: 527 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.1
DANN	Benign	0.74
PhyloP100		-0.23
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: rs633903; hg19: chr9-27196119; COSMIC: COSV66228265; COSMIC: COSV66228265;