rs34038364

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_002253.4(KDR):c.2066C>T(p.Thr689Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,613,602 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 12 hom. )

Consequence

KDR
NM_002253.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter U:1B:2O:1

Conservation

PhyloP100: -0.0930

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0052033663).

BP6

Variant 4-55102430-G-A is Benign according to our data. Variant chr4-55102430-G-A is described in ClinVar as [Benign]. Clinvar id is 134606.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-55102430-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 443 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDR	NM_002253.4 linkuse as main transcript	c.2066C>T	p.Thr689Met	missense_variant	14/30	ENST00000263923.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDR	ENST00000263923.5 linkuse as main transcript	c.2066C>T	p.Thr689Met	missense_variant	14/30	1	NM_002253.4	P1	P35968-1
KDR	ENST00000647068.1 linkuse as main transcript	n.2079C>T		non_coding_transcript_exon_variant	14/30

Frequencies

GnomAD3 genomes

AF:

0.00291

AC:

443

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0138

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00322

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00319

AC:

800

AN:

251160

Hom.:

AF XY:

0.00297

AC XY:

403

AN XY:

135738

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00258

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0152

Gnomad NFE exome

AF:

0.00296

Gnomad OTH exome

AF:

0.00523

GnomAD4 exome

AF:

0.00336

AC:

4916

AN:

1461346

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

2344

AN XY:

726994

show subpopulations

Gnomad4 AFR exome

AF:

0.000389

Gnomad4 AMR exome

AF:

0.00242

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0136

Gnomad4 NFE exome

AF:

0.00349

Gnomad4 OTH exome

AF:

0.00310

GnomAD4 genome

AF:

0.00291

AC:

443

AN:

152256

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

263

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.000770

Gnomad4 AMR

AF:

0.00242

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0138

Gnomad4 NFE

AF:

0.00322

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00287

Hom.:

Bravo

AF:

0.00209

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00407

AC:

ExAC

AF:

0.00287

AC:

349

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00327

EpiControl

AF:

0.00344

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:2Other:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The KDR p.Thr689Met variant was not identified in the literature but was identified in dbSNP (ID: rs34038364), ClinVar (classified as uncertain significance by Department of Genetics, Reproduction and Fetal Medicine, Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocâˆšâ‰ o/CSIC/University of Seville) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 916 of 282566 chromosomes (7 homozygous) at a frequency of 0.003242 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 370 of 25118 chromosomes (freq: 0.01473), Other in 40 of 7210 chromosomes (freq: 0.005548), European (non-Finnish) in 392 of 128968 chromosomes (freq: 0.00304), Latino in 92 of 35386 chromosomes (freq: 0.0026), African in 21 of 24964 chromosomes (freq: 0.000841) and Ashkenazi Jewish in 1 of 10360 chromosomes (freq: 0.000097), but was not observed in the East Asian or South Asian populations. The p.Thr689 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Hirschsprung disease, susceptibility to, 1

Uncertain:1

Uncertain significance, no assertion criteria provided

research

Department of Genetics, Reproduction and Fetal Medicine., Institute of Biomedicine of Seville (IBIS), University Hospital Virgen del Rocío/CSIC/University of Seville.

Apr 01, 2015

- -

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

0.070

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

8.5

DANN

Benign

0.87

DEOGEN2

Benign

0.11

T;T

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.36

.;T

MetaRNN

Benign

0.0052

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.97

L;L

MutationTaster

Benign

1.0

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.17

.;N

REVEL

Benign

0.044

Sift

Benign

0.14

.;T

Sift4G

Benign

0.12

.;T

Polyphen

0.025

B;B

Vest4

0.22

MVP

0.082

MPC

0.17

ClinPred

0.0020

GERP RS

3.3

Varity_R

0.13

gMVP

0.43

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