9-27158034-G-A

Variant names:

• chr9-27158034-G-A
• rs759283621
• NM_000459.5:c.256G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000459.5(TEK):​c.256G>A​(p.Val86Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,461,882 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: TEK NM_000459.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.77
• Publications: 2 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: Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
• 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), PanelApp Australia
• congenital glaucoma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 29 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEK	NM_000459.5	MANE Select	c.256G>A	p.Val86Ile	missense	Exon 2 of 23	NP_000450.3	Q02763-1
	TEK	NM_001375475.1		c.256G>A	p.Val86Ile	missense	Exon 2 of 23	NP_001362404.1
	TEK	NM_001290077.2		c.256G>A	p.Val86Ile	missense	Exon 2 of 22	NP_001277006.2	Q02763-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEK	ENST00000380036.10	TSL:1 MANE Select	c.256G>A	p.Val86Ile	missense	Exon 2 of 23	ENSP00000369375.4	Q02763-1
	TEK	ENST00000519080.1	TSL:1	c.53-11461G>A		intron	N/A	ENSP00000428337.1	E5RIV9
	TEK	ENST00000923267.1		c.256G>A	p.Val86Ile	missense	Exon 2 of 23	ENSP00000593326.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251438 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727242

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1112002

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000244 Hom.: 0

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Multiple cutaneous and mucosal venous malformations (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.016	T
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.029	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	0.81	L
PhyloP100		6.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.62	N
REVEL	Uncertain	0.36
Sift	Benign	0.041	D
Sift4G	Benign	0.28	T
Polyphen		0.97	D
Vest4		0.51
MutPred		0.67		Gain of methylation at K89 (P = 0.114)
MVP		0.60
MPC		0.62
ClinPred		0.39	T
GERP RS		5.9
Varity_R		0.14
gMVP		0.31
Mutation Taster		=55/45	polymorphism

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: rs759283621; hg19: chr9-27158032;