rs628873

Variant names:

• chr9-27155546-C-T
• rs628873
• NM_000459.5:c.53-2285C>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.53-2285C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 152,214 control chromosomes in the GnomAD database, including 1,725 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 0.13 (1725 hom., cov: 33)
• Consequence: TEK NM_000459.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.819
• Publications: 7 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.289 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEK	NM_000459.5	c.53-2285C>T		intron_variant	Intron 1 of 22	ENST00000380036.10	NP_000450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEK	ENST00000380036.10	c.53-2285C>T		intron_variant	Intron 1 of 22	1	NM_000459.5	ENSP00000369375.4

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19983 AN: 152096 Hom.: 1718 Cov.: 33

Gnomad AFR AF: 0.209

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.0767

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.303

Gnomad FIN AF: 0.0755

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0754

Gnomad OTH AF: 0.113

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

GnomAD4 genome AF: 0.131 AC: 20006 AN: 152214 Hom.: 1725 Cov.: 33 AF XY: 0.134 AC XY: 9951 AN XY: 74410

African (AFR) AF: 0.209 AC: 8692 AN: 41516

American (AMR) AF: 0.125 AC: 1917 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0767 AC: 266 AN: 3468

East Asian (EAS) AF: 0.275 AC: 1424 AN: 5186

South Asian (SAS) AF: 0.302 AC: 1455 AN: 4812

European-Finnish (FIN) AF: 0.0755 AC: 800 AN: 10592

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0754 AC: 5130 AN: 68026

Other (OTH) AF: 0.116 AC: 245 AN: 2116

Alfa AF: 0.0988 Hom.: 565

Bravo AF: 0.134

Asia WGS AF: 0.281 AC: 977 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.7
DANN	Benign	0.56
PhyloP100		-0.82
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: rs628873; hg19: chr9-27155544;