9-27126417-G-T

Variant names:

• chr9-27126417-G-T
• rs1334809
• NM_000459.5:c.52+16775G>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.52+16775G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 152,096 control chromosomes in the GnomAD database, including 2,591 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 0.15 (2591 hom., cov: 33)
• Consequence: TEK NM_000459.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.76
• Publications: 8 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.583 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000459.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEK	NM_000459.5	MANE Select	c.52+16775G>T		intron	N/A	NP_000450.3
	TEK	NM_001375475.1		c.52+16775G>T		intron	N/A	NP_001362404.1
	TEK	NM_001290077.2		c.52+16775G>T		intron	N/A	NP_001277006.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEK	ENST00000380036.10	TSL:1 MANE Select	c.52+16775G>T		intron	N/A	ENSP00000369375.4
	TEK	ENST00000519080.1	TSL:1	c.52+16775G>T		intron	N/A	ENSP00000428337.1
	TEK	ENST00000406359.8	TSL:2	c.52+16775G>T		intron	N/A	ENSP00000383977.4

Frequencies

GnomAD3 genomes AF: 0.149 AC: 22662 AN: 151978 Hom.: 2588 Cov.: 33

Gnomad AFR AF: 0.0907

Gnomad AMI AF: 0.0991

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.0900

Gnomad EAS AF: 0.601

Gnomad SAS AF: 0.454

Gnomad FIN AF: 0.198

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.127

Gnomad OTH AF: 0.138

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

GnomAD4 genome AF: 0.149 AC: 22671 AN: 152096 Hom.: 2591 Cov.: 33 AF XY: 0.160 AC XY: 11873 AN XY: 74372

African (AFR) AF: 0.0906 AC: 3762 AN: 41508

American (AMR) AF: 0.143 AC: 2184 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0900 AC: 312 AN: 3466

East Asian (EAS) AF: 0.601 AC: 3096 AN: 5152

South Asian (SAS) AF: 0.453 AC: 2181 AN: 4812

European-Finnish (FIN) AF: 0.198 AC: 2095 AN: 10584

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.127 AC: 8606 AN: 67982

Other (OTH) AF: 0.142 AC: 299 AN: 2112

Alfa AF: 0.139 Hom.: 3837

Bravo AF: 0.138

Asia WGS AF: 0.476 AC: 1655 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.14
DANN	Benign	0.69
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: rs1334809; hg19: chr9-27126415;