rs639225

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr9-27202872-A-G
• chr9-27202872-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000459.5(TEK):​c.1962A>G​(p.Ser654Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,613,684 control chromosomes in the GnomAD database, including 185,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16319 hom., cov: 32)
  • Exomes 𝑓: 0.48 (168898 hom.)
• Consequence: TEK NM_000459.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• 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: 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 9-27202872-A-G is Benign according to our data. Variant chr9-27202872-A-G is described in ClinVar as Benign. ClinVar VariationId is 366434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.485 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TEK	NM_000459.5	MANE Select	c.1962A>G	p.Ser654Ser	synonymous	Exon 13 of 23	NP_000450.3	Q02763-1
	TEK	NM_001375475.1		c.1962A>G	p.Ser654Ser	synonymous	Exon 13 of 23	NP_001362404.1
	TEK	NM_001290077.2		c.1833A>G	p.Ser611Ser	synonymous	Exon 12 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.1962A>G	p.Ser654Ser	synonymous	Exon 13 of 23	ENSP00000369375.4	Q02763-1
	TEK	ENST00000519080.1	TSL:1	c.1392A>G	p.Ser464Ser	synonymous	Exon 10 of 10	ENSP00000428337.1	E5RIV9
	TEK	ENST00000923267.1		c.2004A>G	p.Ser668Ser	synonymous	Exon 13 of 23	ENSP00000593326.1

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69340 AN: 151942 Hom.: 16313 Cov.: 32

Gnomad AFR AF: 0.366

Gnomad AMI AF: 0.501

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.642

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.490

Gnomad OTH AF: 0.432

GnomAD2 exomes AF: 0.471 AC: 118122 AN: 251000 AF XY: 0.466

Gnomad AFR exome AF: 0.361

Gnomad AMR exome AF: 0.532

Gnomad ASJ exome AF: 0.386

Gnomad EAS exome AF: 0.393

Gnomad FIN exome AF: 0.627

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.469

GnomAD4 exome AF: 0.477 AC: 697869 AN: 1461624 Hom.: 168898 Cov.: 54 AF XY: 0.475 AC XY: 345034 AN XY: 727118

African (AFR) AF: 0.359 AC: 12025 AN: 33470

American (AMR) AF: 0.523 AC: 23379 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 10204 AN: 26130

East Asian (EAS) AF: 0.384 AC: 15253 AN: 39694

South Asian (SAS) AF: 0.380 AC: 32761 AN: 86254

European-Finnish (FIN) AF: 0.622 AC: 33241 AN: 53412

Middle Eastern (MID) AF: 0.391 AC: 2253 AN: 5768

European-Non Finnish (NFE) AF: 0.486 AC: 540671 AN: 1111790

Other (OTH) AF: 0.465 AC: 28082 AN: 60386

GnomAD4 genome AF: 0.456 AC: 69357 AN: 152060 Hom.: 16319 Cov.: 32 AF XY: 0.462 AC XY: 34350 AN XY: 74308

African (AFR) AF: 0.366 AC: 15169 AN: 41456

American (AMR) AF: 0.486 AC: 7426 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 1290 AN: 3468

East Asian (EAS) AF: 0.402 AC: 2082 AN: 5176

South Asian (SAS) AF: 0.379 AC: 1824 AN: 4816

European-Finnish (FIN) AF: 0.642 AC: 6796 AN: 10580

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.490 AC: 33299 AN: 67976

Other (OTH) AF: 0.429 AC: 903 AN: 2106

Alfa AF: 0.463 Hom.: 30018

Bravo AF: 0.442

Asia WGS AF: 0.425 AC: 1480 AN: 3478

EpiCase AF: 0.464

EpiControl AF: 0.462

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Multiple cutaneous and mucosal venous malformations (3)
-	-	3	not provided (3)
-	-	1	Glaucoma 3, primary congenital, E (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.36
DANN	Benign	0.58
PhyloP100		-3.6
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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; COSMIC: COSV66227391; COSMIC: COSV66227391;