chr9-27158022-T-C

Position:

• chr9-27158022-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_000459.5(TEK):​c.244T>C​(p.Trp82Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,960 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: TEK NM_000459.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17667043).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000105 (16/152078) while in subpopulation AFR AF= 0.00029 (12/41410). AF 95% confidence interval is 0.000167. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TEK	NM_000459.5	c.244T>C	p.Trp82Arg	missense_variant	2/23	ENST00000380036.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TEK	ENST00000380036.10	c.244T>C	p.Trp82Arg	missense_variant	2/23	1	NM_000459.5	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152078 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251398 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135862

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 727242

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152078 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74296

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000955

Alfa AF: 0.000197 Hom.: 0

Bravo AF: 0.000121

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 17, 2021

The c.244T>C (p.W82R) alteration is located in exon 2 (coding exon 2) of the TEK gene. This alteration results from a T to C substitution at nucleotide position 244, causing the tryptophan (W) at amino acid position 82 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.90
DEOGEN2	Benign	0.030	T;T;.
Eigen	Benign	-0.15
Eigen_PC	Benign	0.022
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.79	T;T;T
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.0	.;N;N
MutationTaster	Benign	0.73	D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-2.0	.;N;N
REVEL	Uncertain	0.42
Sift	Benign	0.33	.;T;T
Sift4G	Benign	0.075	T;T;T
Polyphen		0.10	.;B;.
Vest4		0.53
MutPred		0.81		Gain of disorder (P = 0.0082);Gain of disorder (P = 0.0082);Gain of disorder (P = 0.0082);
MVP		0.58
MPC		0.40
ClinPred		0.048	T
GERP RS		4.8
Varity_R		0.32
gMVP		0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs766278026; hg19: chr9-27158020;