rs34231037

Positions:

chr4-55106779-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002253.4(KDR):c.1444T>C(p.Cys482Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0277 in 1,602,386 control chromosomes in the GnomAD database, including 676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.022 ( 58 hom., cov: 32)

Exomes 𝑓: 0.028 ( 618 hom. )

Consequence

KDR
NM_002253.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4O:2

Conservation

PhyloP100: 6.38

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009061545).

BP6

Variant 4-55106779-A-G is Benign according to our data. Variant chr4-55106779-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 12318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-55106779-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0223 (3397/152314) while in subpopulation NFE AF= 0.032 (2174/68026). AF 95% confidence interval is 0.0308. There are 58 homozygotes in gnomad4. There are 1664 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 3397 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDR	NM_002253.4 link	c.1444T>C	p.Cys482Arg	missense_variant	11/30	ENST00000263923.5	NP_002244.1	P35968-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
KDR	ENST00000263923.5 link	c.1444T>C	p.Cys482Arg	missense_variant	11/30	1	NM_002253.4	ENSP00000263923.4	P35968-1
KDR	ENST00000512566.1 link	n.1444T>C		non_coding_transcript_exon_variant	11/13	1
KDR	ENST00000647068.1 link	n.1457T>C		non_coding_transcript_exon_variant	11/30

Frequencies

GnomAD3 genomes

AF:

0.0223

AC:

3398

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00577

Gnomad AMI

AF:

0.114

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.0181

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00724

Gnomad FIN

AF:

0.0483

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0320

Gnomad OTH

AF:

0.0249

GnomAD3 exomes

AF:

0.0230

AC:

5765

AN:

250884

Hom.:

AF XY:

0.0236

AC XY:

3206

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.00555

Gnomad AMR exome

AF:

0.0137

Gnomad ASJ exome

AF:

0.0170

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00683

Gnomad FIN exome

AF:

0.0487

Gnomad NFE exome

AF:

0.0318

Gnomad OTH exome

AF:

0.0259

GnomAD4 exome

AF:

0.0283

AC:

40966

AN:

1450072

Hom.:

618

Cov.:

AF XY:

0.0278

AC XY:

20106

AN XY:

722286

show subpopulations

Gnomad4 AFR exome

AF:

0.00504

Gnomad4 AMR exome

AF:

0.0139

Gnomad4 ASJ exome

AF:

0.0180

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00743

Gnomad4 FIN exome

AF:

0.0409

Gnomad4 NFE exome

AF:

0.0319

Gnomad4 OTH exome

AF:

0.0258

GnomAD4 genome

AF:

0.0223

AC:

3397

AN:

152314

Hom.:

Cov.:

AF XY:

0.0223

AC XY:

1664

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00575

Gnomad4 AMR

AF:

0.0133

Gnomad4 ASJ

AF:

0.0181

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00704

Gnomad4 FIN

AF:

0.0483

Gnomad4 NFE

AF:

0.0320

Gnomad4 OTH

AF:

0.0246

Alfa

AF:

0.0285

Hom.:

Bravo

AF:

0.0193

TwinsUK

AF:

0.0351

AC:

130

ALSPAC

AF:

0.0327

AC:

126

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.0281

AC:

242

ExAC

AF:

0.0223

AC:

2705

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0326

EpiControl

AF:

0.0321

ClinVar

Significance: Likely benign

Submissions summary: Benign:4Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The KDR p.Cys482Arg variant was identified in dbSNP (ID: rs34231037) as well as ClinVar (reported as likely benign by the Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine), Clinvitae, Cosmic (FATHMM prediction of pathogenic (score=0.99)), MutDB (classified as a polymorphism by SwissProt) and LOVD 3.0. The variant was identified in control databases in 6505 of 282288 chromosomes (95 homozygous) at a frequency of 0.023044 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: European (Finnish) in 1202 of 25118 chromosomes (freq: 0.04785), European (non-Finnish) in 4106 of 128738 chromosomes (freq: 0.03189), Other in 179 of 7198 chromosomes (freq: 0.02487), Ashkenazi Jewish in 178 of 10354 chromosomes (freq: 0.01719), Latino in 486 of 35398 chromosomes (freq: 0.01373), South Asian in 209 of 30610 chromosomes (freq: 0.006828) and African in 145 of 24926 chromosomes (freq: 0.005817); it was not observed in the East Asian populations. The variant was identified in the literature where it was identified in a population of patients with Hemangioma at a frequency of 0.044, however it was also identified in a control population at a frequency of 0.041 (Jinnin_2008_18931684). The C482R variant was also found to be associated with soluble VEGFR2 levels and greater sensitivity and response to pazopanib (Maitland_2015_25411163), and was also associated with better sunitinib response (ApellâˆšÂ°niz-Ruiz_2017_28430711). The p.Cys482 residue is conserved across mammals and other organisms, and 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. 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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP(all): 265/13006=2.03% -

Capillary infantile hemangioma

Benign:1Other:1

risk factor, no assertion criteria provided	literature only	OMIM	Nov 01, 2008	- -
Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Uncertain

0.037

BayesDel_noAF

Pathogenic

0.31

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

D;D

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.69

.;T

MetaRNN

Benign

0.0091

T;T

MetaSVM

Uncertain

-0.049

MutationAssessor

Pathogenic

3.1

M;M

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-4.8

.;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.012

.;D

Sift4G

Uncertain

0.0020

.;D

Polyphen

1.0

D;D

Vest4

0.29

MPC

0.90

ClinPred

0.026

GERP RS

5.7

Varity_R

0.84

gMVP

0.90

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