NM_000459.5:c.2687-345C>T

Variant names:

• chr9-27212362-C-T
• rs10757641
• NM_000459.5:c.2687-345C>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.2687-345C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.82 in 152,160 control chromosomes in the GnomAD database, including 51,391 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 0.82 (51391 hom., cov: 32)
• Consequence: TEK NM_000459.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.82
• Publications: 9 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.889 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEK	NM_000459.5	c.2687-345C>T		intron_variant	Intron 16 of 22	ENST00000380036.10	NP_000450.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEK	ENST00000380036.10	c.2687-345C>T		intron_variant	Intron 16 of 22	1	NM_000459.5	ENSP00000369375.4
TEK	ENST00000406359.8	c.2558-345C>T		intron_variant	Intron 15 of 21	2		ENSP00000383977.4
TEK	ENST00000519097.5	c.2243-345C>T		intron_variant	Intron 14 of 20	2		ENSP00000430686.1
TEK	ENST00000615002.4	c.*1188-345C>T		intron_variant	Intron 16 of 22	5		ENSP00000480251.1

Frequencies

GnomAD3 genomes AF: 0.819 AC: 124582 AN: 152042 Hom.: 51333 Cov.: 32

Gnomad AFR AF: 0.897

Gnomad AMI AF: 0.663

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.863

Gnomad EAS AF: 0.884

Gnomad SAS AF: 0.822

Gnomad FIN AF: 0.735

Gnomad MID AF: 0.820

Gnomad NFE AF: 0.771

Gnomad OTH AF: 0.827

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

GnomAD4 genome AF: 0.820 AC: 124700 AN: 152160 Hom.: 51391 Cov.: 32 AF XY: 0.821 AC XY: 61046 AN XY: 74394

African (AFR) AF: 0.897 AC: 37261 AN: 41538

American (AMR) AF: 0.860 AC: 13143 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.863 AC: 2996 AN: 3470

East Asian (EAS) AF: 0.883 AC: 4560 AN: 5162

South Asian (SAS) AF: 0.822 AC: 3956 AN: 4812

European-Finnish (FIN) AF: 0.735 AC: 7775 AN: 10578

Middle Eastern (MID) AF: 0.820 AC: 241 AN: 294

European-Non Finnish (NFE) AF: 0.771 AC: 52416 AN: 67998

Other (OTH) AF: 0.828 AC: 1749 AN: 2112

Alfa AF: 0.800 Hom.: 70442

Bravo AF: 0.831

Asia WGS AF: 0.851 AC: 2953 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.17
DANN	Benign	0.64
PhyloP100		-1.8
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: rs10757641; hg19: chr9-27212360;