9-27187218-C-G

Variant names:

• chr9-27187218-C-G
• rs489347
• NM_000459.5:c.1327+1589C>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.1327+1589C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.676 in 152,054 control chromosomes in the GnomAD database, including 35,116 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 0.68 (35116 hom., cov: 33)
• Consequence: TEK NM_000459.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0950
• Publications: 11 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=-0.86).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.733 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.1327+1589C>G		intron	N/A	NP_000450.3
	TEK	NM_001375475.1		c.1327+1589C>G		intron	N/A	NP_001362404.1
	TEK	NM_001290077.2		c.1198+1589C>G		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.1327+1589C>G		intron	N/A	ENSP00000369375.4
	TEK	ENST00000519080.1	TSL:1	c.757+1589C>G		intron	N/A	ENSP00000428337.1
	TEK	ENST00000406359.8	TSL:2	c.1198+1589C>G		intron	N/A	ENSP00000383977.4

Frequencies

GnomAD3 genomes AF: 0.676 AC: 102735 AN: 151934 Hom.: 35080 Cov.: 33

Gnomad AFR AF: 0.687

Gnomad AMI AF: 0.680

Gnomad AMR AF: 0.744

Gnomad ASJ AF: 0.659

Gnomad EAS AF: 0.382

Gnomad SAS AF: 0.702

Gnomad FIN AF: 0.675

Gnomad MID AF: 0.643

Gnomad NFE AF: 0.676

Gnomad OTH AF: 0.690

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

GnomAD4 genome AF: 0.676 AC: 102825 AN: 152054 Hom.: 35116 Cov.: 33 AF XY: 0.676 AC XY: 50272 AN XY: 74330

African (AFR) AF: 0.687 AC: 28491 AN: 41480

American (AMR) AF: 0.744 AC: 11356 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.659 AC: 2287 AN: 3470

East Asian (EAS) AF: 0.382 AC: 1972 AN: 5160

South Asian (SAS) AF: 0.702 AC: 3384 AN: 4822

European-Finnish (FIN) AF: 0.675 AC: 7140 AN: 10578

Middle Eastern (MID) AF: 0.634 AC: 185 AN: 292

European-Non Finnish (NFE) AF: 0.676 AC: 45936 AN: 67966

Other (OTH) AF: 0.688 AC: 1454 AN: 2114

Alfa AF: 0.581 Hom.: 1663

Bravo AF: 0.681

Asia WGS AF: 0.593 AC: 2064 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	11
DANN	Benign	0.69
PhyloP100		0.095
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: rs489347; hg19: chr9-27187216; COSMIC: COSV66228244;