chr9-27202872-A-T

Variant names:

• chr9-27202872-A-T
• rs639225
• NM_000459.5:c.1962A>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000459.5(TEK):​c.1962A>T​(p.Ser654Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S654S) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TEK NM_000459.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.62
• Publications: 36 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP7: Synonymous conserved (PhyloP=-3.62 with no splicing effect.

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.1962A>T	p.Ser654Ser	synonymous	Exon 13 of 23	NP_000450.3
	TEK	NM_001375475.1		c.1962A>T	p.Ser654Ser	synonymous	Exon 13 of 23	NP_001362404.1
	TEK	NM_001290077.2		c.1833A>T	p.Ser611Ser	synonymous	Exon 12 of 22	NP_001277006.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEK	ENST00000380036.10	TSL:1 MANE Select	c.1962A>T	p.Ser654Ser	synonymous	Exon 13 of 23	ENSP00000369375.4
	TEK	ENST00000519080.1	TSL:1	c.1392A>T	p.Ser464Ser	synonymous	Exon 10 of 10	ENSP00000428337.1
	TEK	ENST00000406359.8	TSL:2	c.1833A>T	p.Ser611Ser	synonymous	Exon 12 of 22	ENSP00000383977.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 54

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.27
DANN	Benign	0.67
PhyloP100		-3.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs639225; hg19: chr9-27202870;