chr4-55125294-C-A

Variant names:

• chr4-55125294-C-A
• rs56233104
• NM_002253.4:c.-1G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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 no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 1.94
• Publications: 10 publications found

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• 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 rank	MANE	Protein	UniProt
KDR	NM_002253.4	c.-1G>T		5_prime_UTR_variant	Exon 1 of 30	ENST00000263923.5	NP_002244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDR	ENST00000263923.5	c.-1G>T		5_prime_UTR_variant	Exon 1 of 30	1	NM_002253.4	ENSP00000263923.4
KDR	ENST00000512566.1	n.-1G>T		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

GnomAD2 exomes AF: 0.0368 AC: 8907 AN: 241940 AF XY: 0.0370

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 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

African (AFR) AF: 0.0163 AC: 544 AN: 33456

American (AMR) AF: 0.0253 AC: 1123 AN: 44458

Ashkenazi Jewish (ASJ) AF: 0.0469 AC: 1220 AN: 26024

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39636

South Asian (SAS) AF: 0.0119 AC: 1014 AN: 85554

European-Finnish (FIN) AF: 0.0222 AC: 1171 AN: 52756

Middle Eastern (MID) AF: 0.0544 AC: 313 AN: 5754

European-Non Finnish (NFE) AF: 0.0602 AC: 66829 AN: 1111026

Other (OTH) AF: 0.0420 AC: 2532 AN: 60238

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

African (AFR) AF: 0.0167 AC: 696 AN: 41578

American (AMR) AF: 0.0328 AC: 502 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0447 AC: 155 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5168

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4828

European-Finnish (FIN) AF: 0.0186 AC: 198 AN: 10630

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0573 AC: 3900 AN: 68028

Other (OTH) AF: 0.0388 AC: 82 AN: 2116

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: no assertion criteria provided

Submissions by phenotype

KDR-related disorder Benign:1

Jul 23, 2024

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
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.85
PhyloP100		1.9
PromoterAI		0.035	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56233104; hg19: chr4-55991461; COSMIC: COSV55759034;