rs56233104

chr4-55125294-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_002253.4(KDR):c.-1G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0499 in 1,611,238 control chromosomes in the GnomAD database, including 2,284 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.037 (142 hom., cov: 33)
  • Exomes 𝑓: 0.051 (2142 hom.)
• Consequence: KDR NM_002253.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: 1.94

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 4-55125294-C-A is Benign according to our data. Variant chr4-55125294-C-A is described in ClinVar as [Benign]. Clinvar id is 135552.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-55125294-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDR	NM_002253.4	c.-1G>T		5_prime_UTR_variant	1/30	ENST00000263923.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDR	ENST00000263923.5	c.-1G>T		5_prime_UTR_variant	1/30	1	NM_002253.4	P1
KDR	ENST00000512566.1			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0371 AC: 5641 AN: 152218 Hom.: 142 Cov.: 33

Gnomad AFR AF: 0.0168

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0328

Gnomad ASJ AF: 0.0447

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0186

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0573

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0368 AC: 8907 AN: 241940 Hom.: 199 AF XY: 0.0370 AC XY: 4873 AN XY: 131526

Gnomad AFR exome AF: 0.0156

Gnomad AMR exome AF: 0.0234

Gnomad ASJ exome AF: 0.0462

Gnomad EAS exome AF: 0.000332

Gnomad SAS exome AF: 0.0115

Gnomad FIN exome AF: 0.0184

Gnomad NFE exome AF: 0.0589

Gnomad OTH exome AF: 0.0448

GnomAD4 exome AF: 0.0512 AC: 74751 AN: 1458902 Hom.: 2142 Cov.: 32 AF XY: 0.0502 AC XY: 36439 AN XY: 725528

Gnomad4 AFR exome AF: 0.0163

Gnomad4 AMR exome AF: 0.0253

Gnomad4 ASJ exome AF: 0.0469

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0119

Gnomad4 FIN exome AF: 0.0222

Gnomad4 NFE exome AF: 0.0602

Gnomad4 OTH exome AF: 0.0420

GnomAD4 genome AF: 0.0370 AC: 5643 AN: 152336 Hom.: 142 Cov.: 33 AF XY: 0.0340 AC XY: 2530 AN XY: 74502

Gnomad4 AFR AF: 0.0167

Gnomad4 AMR AF: 0.0328

Gnomad4 ASJ AF: 0.0447

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.0186

Gnomad4 NFE AF: 0.0573

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0503 Hom.: 87

Bravo AF: 0.0372

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

KDR-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 09, 2019

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

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
Cadd	Benign	18
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs56233104; hg19: chr4-55991461; COSMIC: COSV55759034; COSMIC: COSV55759034;