chr9-27149671-T-C

Variant names:

• chr9-27149671-T-C
• rs4878149
• NM_000459.5:c.53-8160T>C

Variant summary

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

The NM_000459.5(TEK):​c.53-8160T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.179 in 152,166 control chromosomes in the GnomAD database, including 3,160 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 0.18 (3160 hom., cov: 32)
• Consequence: TEK NM_000459.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0440
• 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.245 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TEK	NM_000459.5	c.53-8160T>C		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.53-8160T>C		intron_variant	Intron 1 of 22	1	NM_000459.5	ENSP00000369375.4

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27204 AN: 152048 Hom.: 3151 Cov.: 32

Gnomad AFR AF: 0.0460

Gnomad AMI AF: 0.401

Gnomad AMR AF: 0.238

Gnomad ASJ AF: 0.147

Gnomad EAS AF: 0.0468

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.250

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.189

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

GnomAD4 genome AF: 0.179 AC: 27214 AN: 152166 Hom.: 3160 Cov.: 32 AF XY: 0.181 AC XY: 13434 AN XY: 74388

African (AFR) AF: 0.0458 AC: 1903 AN: 41518

American (AMR) AF: 0.239 AC: 3651 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 510 AN: 3472

East Asian (EAS) AF: 0.0467 AC: 242 AN: 5178

South Asian (SAS) AF: 0.112 AC: 539 AN: 4812

European-Finnish (FIN) AF: 0.250 AC: 2646 AN: 10586

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16894 AN: 67998

Other (OTH) AF: 0.189 AC: 399 AN: 2110

Alfa AF: 0.226 Hom.: 13983

Bravo AF: 0.176

Asia WGS AF: 0.0830 AC: 288 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.2
DANN	Benign	0.56
PhyloP100		-0.044
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: rs4878149; hg19: chr9-27149669; COSMIC: COSV66228219;