chr9-27118809-A-G

Variant names:

• chr9-27118809-A-G
• rs621786
• NM_000459.5:c.52+9167A>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.52+9167A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.396 in 151,840 control chromosomes in the GnomAD database, including 12,381 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 0.40 (12381 hom., cov: 32)
• Consequence: TEK NM_000459.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.325
• 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.679 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEK	NM_000459.5	c.52+9167A>G		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.52+9167A>G		intron_variant	Intron 1 of 22	1	NM_000459.5	ENSP00000369375.4

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60022 AN: 151720 Hom.: 12374 Cov.: 32

Gnomad AFR AF: 0.379

Gnomad AMI AF: 0.547

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.699

Gnomad SAS AF: 0.621

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.377

Gnomad OTH AF: 0.409

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

GnomAD4 genome AF: 0.396 AC: 60061 AN: 151840 Hom.: 12381 Cov.: 32 AF XY: 0.402 AC XY: 29846 AN XY: 74182

African (AFR) AF: 0.379 AC: 15670 AN: 41386

American (AMR) AF: 0.320 AC: 4878 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1405 AN: 3468

East Asian (EAS) AF: 0.698 AC: 3600 AN: 5154

South Asian (SAS) AF: 0.621 AC: 2985 AN: 4808

European-Finnish (FIN) AF: 0.417 AC: 4385 AN: 10516

Middle Eastern (MID) AF: 0.439 AC: 129 AN: 294

European-Non Finnish (NFE) AF: 0.377 AC: 25641 AN: 67936

Other (OTH) AF: 0.413 AC: 871 AN: 2108

Alfa AF: 0.386 Hom.: 51806

Bravo AF: 0.383

Asia WGS AF: 0.618 AC: 2152 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	4.7
DANN	Benign	0.60
PhyloP100		0.33
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: rs621786; hg19: chr9-27118807; COSMIC: COSV66233047;