NM_002253.4:c.1416A>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_002253.4(KDR):c.1416A>T(p.Gln472His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,599,452 control chromosomes in the GnomAD database, including 44,436 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.20 ( 3613 hom., cov: 33)

Exomes 𝑓: 0.23 ( 40823 hom. )

Consequence

KDR
NM_002253.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1O:1

Conservation

PhyloP100: -0.0390

Publications

365 publications found

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 Gene-Disease associations (from GenCC):

pulmonary arterial hypertension
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen

KDR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=2.7933717E-4).

BP6

Variant 4-55106807-T-A is Benign according to our data. Variant chr4-55106807-T-A is described in ClinVar as Benign. ClinVar VariationId is 134603.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDR	NM_002253.4 link	c.1416A>T	p.Gln472His	missense_variant	Exon 11 of 30	ENST00000263923.5	NP_002244.1	P35968-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KDR	ENST00000263923.5 link	c.1416A>T	p.Gln472His	missense_variant	Exon 11 of 30	1	NM_002253.4	ENSP00000263923.4	P35968-1
KDR	ENST00000512566.1 link	n.1416A>T		non_coding_transcript_exon_variant	Exon 11 of 13	1
KDR	ENST00000647068.1 link	n.1429A>T		non_coding_transcript_exon_variant	Exon 11 of 30

Frequencies

GnomAD3 genomes

AF:

0.204

AC:

30976

AN:

152078

Hom.:

3610

Cov.:

show subpopulations

Gnomad AFR

AF:

0.107

Gnomad AMI

AF:

0.245

Gnomad AMR

AF:

0.150

Gnomad ASJ

AF:

0.201

Gnomad EAS

AF:

0.467

Gnomad SAS

AF:

0.169

Gnomad FIN

AF:

0.303

Gnomad MID

AF:

0.161

Gnomad NFE

AF:

0.242

Gnomad OTH

AF:

0.201

GnomAD2 exomes

AF:

0.223

AC:

55838

AN:

250700

AF XY:

0.225

show subpopulations

Gnomad AFR exome

AF:

0.103

Gnomad AMR exome

AF:

0.102

Gnomad ASJ exome

AF:

0.197

Gnomad EAS exome

AF:

0.479

Gnomad FIN exome

AF:

0.298

Gnomad NFE exome

AF:

0.239

Gnomad OTH exome

AF:

0.215

GnomAD4 exome

AF:

0.230

AC:

332586

AN:

1447256

Hom.:

40823

Cov.:

AF XY:

0.230

AC XY:

165501

AN XY:

720958

show subpopulations

African (AFR)

AF:

0.102

AC:

3401

AN:

33292

American (AMR)

AF:

0.107

AC:

4786

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.202

AC:

5263

AN:

26056

East Asian (EAS)

AF:

0.435

AC:

17207

AN:

39538

South Asian (SAS)

AF:

0.164

AC:

14083

AN:

86046

European-Finnish (FIN)

AF:

0.284

AC:

15152

AN:

53382

Middle Eastern (MID)

AF:

0.169

AC:

968

AN:

5744

European-Non Finnish (NFE)

AF:

0.235

AC:

258045

AN:

1098622

Other (OTH)

AF:

0.228

AC:

13681

AN:

59894

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

11005

22010

33015

44020

55025

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8644

17288

25932

34576

43220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.204

AC:

30991

AN:

152196

Hom.:

3613

Cov.:

AF XY:

0.207

AC XY:

15364

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.107

AC:

4428

AN:

41570

American (AMR)

AF:

0.149

AC:

2284

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.201

AC:

699

AN:

3472

East Asian (EAS)

AF:

0.467

AC:

2412

AN:

5162

South Asian (SAS)

AF:

0.169

AC:

817

AN:

4824

European-Finnish (FIN)

AF:

0.303

AC:

3199

AN:

10574

Middle Eastern (MID)

AF:

0.170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.242

AC:

16444

AN:

67984

Other (OTH)

AF:

0.206

AC:

435

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1231

2462

3694

4925

6156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

332

664

996

1328

1660

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.240

Hom.:

3513

Bravo

AF:

0.188

TwinsUK

AF:

0.237

AC:

878

ALSPAC

AF:

0.242

AC:

931

ESP6500AA

AF:

0.110

AC:

485

ESP6500EA

AF:

0.237

AC:

2037

ExAC

AF:

0.219

AC:

26633

Asia WGS

AF:

0.317

AC:

1101

AN:

3478

EpiCase

AF:

0.240

EpiControl

AF:

0.239

ClinVar

Significance: Benign

Submissions summary: Benign:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

KDR-related disorder

Benign:1

Aug 02, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Other:1

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.47

CADD

Benign

1.8

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.14

T;T

Eigen

Benign

-0.89

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.068

LIST_S2

Benign

0.36

.;T

MetaRNN

Benign

0.00028

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.6

L;L

PhyloP100

-0.039

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.3

.;N

REVEL

Benign

0.17

Sift

Benign

0.033

.;D

Sift4G

Uncertain

0.027

.;D

Polyphen

0.0030

B;B

Vest4

0.034

MutPred

0.22

Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);

MPC

0.15

ClinPred

0.0095

GERP RS

-1.8

Varity_R

0.029

gMVP

0.59

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over