rs139047809

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002253.4(KDR):c.170G>C(p.Arg57Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,614,064 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00099 ( 10 hom. )

Consequence

KDR
NM_002253.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1O:1

Conservation

PhyloP100: 2.47

Variant links:

Genes affected

KDR (HGNC:6307): (kinase insert domain receptor) Vascular endothelial growth factor (VEGF) is a major growth factor for endothelial cells. This gene encodes one of the two receptors of the VEGF. This receptor, known as kinase insert domain receptor, is a type III receptor tyrosine kinase. It functions as the main mediator of VEGF-induced endothelial proliferation, survival, migration, tubular morphogenesis and sprouting. The signalling and trafficking of this receptor are regulated by multiple factors, including Rab GTPase, P2Y purine nucleotide receptor, integrin alphaVbeta3, T-cell protein tyrosine phosphatase, etc.. Mutations of this gene are implicated in infantile capillary hemangiomas. [provided by RefSeq, May 2009]

KDR links:

KDR (HGNC:):

KDR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0048685074).

BS2

High AC in GnomAd4 at 203 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDR	NM_002253.4 linkuse as main transcript	c.170G>C	p.Arg57Thr	missense_variant	3/30	ENST00000263923.5	NP_002244.1	P35968-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KDR	ENST00000263923.5 linkuse as main transcript	c.170G>C	p.Arg57Thr	missense_variant	3/30	1	NM_002253.4	ENSP00000263923.4	P35968-1
KDR	ENST00000512566.1 linkuse as main transcript	n.170G>C		non_coding_transcript_exon_variant	3/13	1
KDR	ENST00000647068.1 linkuse as main transcript	n.183G>C		non_coding_transcript_exon_variant	3/30

Frequencies

GnomAD3 genomes

AF:

0.00133

AC:

203

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00393

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.00188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00123

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.00123

AC:

309

AN:

251422

Hom.:

AF XY:

0.00135

AC XY:

183

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00113

Gnomad ASJ exome

AF:

0.00387

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00363

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.000730

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.000993

AC:

1452

AN:

1461708

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

828

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00105

Gnomad4 ASJ exome

AF:

0.00417

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00358

Gnomad4 FIN exome

AF:

0.00110

Gnomad4 NFE exome

AF:

0.000791

Gnomad4 OTH exome

AF:

0.000778

GnomAD4 genome

AF:

0.00133

AC:

203

AN:

152356

Hom.:

Cov.:

AF XY:

0.00174

AC XY:

130

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.00392

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00476

Gnomad4 FIN

AF:

0.00188

Gnomad4 NFE

AF:

0.00123

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.00113

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.00121

AC:

147

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.000889

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The KDR p.Arg57Thr variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs139047809), ClinVar (submitted by ITMI with no classification) and Cosmic (FATHM prediction: pathogenic; score=0.98). The variant was also identified in control databases in 349 of 282816 chromosomes (5 homozygous) at a frequency of 0.001234 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 39 of 10370 chromosomes (freq: 0.003761), South Asian in 111 of 30616 chromosomes (freq: 0.003626), Other in 12 of 7226 chromosomes (freq: 0.001661), European (Finnish) in 32 of 25122 chromosomes (freq: 0.001274), Latino in 39 of 35410 chromosomes (freq: 0.001101), European (non-Finnish) in 115 of 129168 chromosomes (freq: 0.00089) and African in 1 of 24950 chromosomes (freq: 0.00004), but was not observed in the East Asian population. The p.Arg57 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.21

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.86

.;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.0049

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.5

.;N

REVEL

Benign

0.16

Sift

Benign

0.13

.;T

Sift4G

Benign

0.47

.;T

Polyphen

0.57

P;P

Vest4

0.63

MVP

0.10

MPC

0.37

ClinPred

0.073

GERP RS

3.3

Varity_R

0.071

gMVP

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over