9-27109628-G-A

Variant names:

• chr9-27109628-G-A
• rs201171013
• NM_000459.5:c.38G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_000459.5(TEK):​c.38G>A​(p.Ser13Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S13I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: TEK NM_000459.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.79
• Publications: 0 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.28684634).
• BS2: High AC in GnomAdExome4 at 6 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.38G>A	p.Ser13Asn	missense	Exon 1 of 23	NP_000450.3	Q02763-1
	TEK	NM_001375475.1		c.38G>A	p.Ser13Asn	missense	Exon 1 of 23	NP_001362404.1
	TEK	NM_001290077.2		c.38G>A	p.Ser13Asn	missense	Exon 1 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.38G>A	p.Ser13Asn	missense	Exon 1 of 23	ENSP00000369375.4	Q02763-1
	TEK	ENST00000519080.1	TSL:1	c.38G>A	p.Ser13Asn	missense	Exon 1 of 10	ENSP00000428337.1	E5RIV9
	TEK	ENST00000923267.1		c.38G>A	p.Ser13Asn	missense	Exon 1 of 23	ENSP00000593326.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461872 Hom.: 0 Cov.: 30 AF XY: 0.00000688 AC XY: 5 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111994

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.029	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.34	T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.097
Sift	Benign	0.071	T
Sift4G	Uncertain	0.048	D
Polyphen		0.90	P
Vest4		0.33
MutPred		0.37		Loss of sheet (P = 0.0025)
MVP		0.44
MPC		0.19
ClinPred		0.54	D
GERP RS		5.5
PromoterAI		-0.033	Neutral
Varity_R		0.19
gMVP		0.30
Mutation Taster		=71/29	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: rs201171013; hg19: chr9-27109626;