rs387906745

Variant names:

• chr9-27212764-G-A
• rs387906745
• NM_000459.5:c.2744G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000459.5(TEK):​c.2744G>A​(p.Arg915His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,856 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R915C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TEK NM_000459.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.96
• Publications: 8 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: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000459.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-27212763-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 981227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 9-27212764-G-A is Pathogenic according to our data. Variant chr9-27212764-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30054.Status of the report is criteria_provided_single_submitter, 1 stars.

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.2744G>A	p.Arg915His	missense	Exon 17 of 23	NP_000450.3
	TEK	NM_001375475.1		c.2741G>A	p.Arg914His	missense	Exon 17 of 23	NP_001362404.1
	TEK	NM_001290077.2		c.2615G>A	p.Arg872His	missense	Exon 16 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.2744G>A	p.Arg915His	missense	Exon 17 of 23	ENSP00000369375.4
	TEK	ENST00000406359.8	TSL:2	c.2615G>A	p.Arg872His	missense	Exon 16 of 22	ENSP00000383977.4
	TEK	ENST00000519097.5	TSL:2	c.2300G>A	p.Arg767His	missense	Exon 15 of 21	ENSP00000430686.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461856 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727238

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: 39690

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111994

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Multiple cutaneous and mucosal venous malformations (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.78	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Benign	1.5	L
PhyloP100		10
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.87
MutPred		0.89		Gain of ubiquitination at K916 (P = 0.0872)
MVP		0.99
MPC		2.4
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.74
gMVP		0.67
Mutation Taster		=7/93	disease causing (ClinVar)

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: rs387906745; hg19: chr9-27212762; COSMIC: COSV66230204; COSMIC: COSV66230204;