rs34231037

chr4-55106779-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3 O:2
• Conservation: PhyloP100: 6.38

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]

ACMG classification

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 GnomAd at 3398 AD gene.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDR	ENST00000263923.5	c.1444T>C	p.Cys482Arg	missense_variant	11/30	1	NM_002253.4	P1
KDR	ENST00000512566.1	n.1444T>C		non_coding_transcript_exon_variant	11/13	1
KDR	ENST00000647068.1	n.1457T>C		non_coding_transcript_exon_variant	11/30

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3398 AN: 152196 Hom.: 58 Cov.: 32

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.: 81 AF XY: 0.0236 AC XY: 3206 AN XY: 135604

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.: 28 AF XY: 0.0278 AC XY: 20106 AN XY: 722286

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.: 58 Cov.: 32 AF XY: 0.0223 AC XY: 1664 AN XY: 74470

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.: 88

Bravo AF: 0.0193

TwinsUK AF: 0.0351 AC: 130

ALSPAC AF: 0.0327 AC: 126

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0281 AC: 242

ExAC AF: 0.0223 AC: 2705

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0326

EpiControl AF: 0.0321

ClinVar

Significance: Likely benign

Submissions summary: Benign:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1 Other:1

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% -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Capillary infantile hemangioma Benign:1 Other: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	- -

not provided Benign:1

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 (Apell√°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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Pathogenic	0.31
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0091	T;T
MetaSVM	Uncertain	-0.049	T
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.58	T
Polyphen		1.0	D;D
Vest4		0.29
MPC		0.90
ClinPred		0.026	T
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

Other links and lift over

dbSNP: rs34231037; hg19: chr4-55972946; COSMIC: COSV55778415;