4-55114289-C-T

Variant names:

• chr4-55114289-C-T
• rs2305949
• NM_002253.4:c.659-24G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002253.4(KDR):​c.659-24G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,609,320 control chromosomes in the GnomAD database, including 33,028 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 0.16 (2237 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30791 hom.)
• Consequence: KDR NM_002253.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.860
• Publications: 28 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.203 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002253.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDR	NM_002253.4	MANE Select	c.659-24G>A		intron	N/A	NP_002244.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDR	ENST00000263923.5	TSL:1 MANE Select	c.659-24G>A		intron	N/A	ENSP00000263923.4
	KDR	ENST00000512566.1	TSL:1	n.659-24G>A		intron	N/A
	KDR	ENST00000922964.1		c.659-24G>A		intron	N/A	ENSP00000593023.1

Frequencies

GnomAD3 genomes AF: 0.161 AC: 24560 AN: 152078 Hom.: 2231 Cov.: 32

Gnomad AFR AF: 0.0743

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.303

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.164

Gnomad MID AF: 0.244

Gnomad NFE AF: 0.206

Gnomad OTH AF: 0.177

GnomAD2 exomes AF: 0.178 AC: 44618 AN: 250184 AF XY: 0.184

Gnomad AFR exome AF: 0.0749

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.296

Gnomad EAS exome AF: 0.180

Gnomad FIN exome AF: 0.166

Gnomad NFE exome AF: 0.206

Gnomad OTH exome AF: 0.195

GnomAD4 exome AF: 0.201 AC: 293200 AN: 1457124 Hom.: 30791 Cov.: 32 AF XY: 0.202 AC XY: 146389 AN XY: 725170

African (AFR) AF: 0.0707 AC: 2361 AN: 33398

American (AMR) AF: 0.106 AC: 4729 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 7732 AN: 26104

East Asian (EAS) AF: 0.158 AC: 6249 AN: 39652

South Asian (SAS) AF: 0.181 AC: 15611 AN: 86140

European-Finnish (FIN) AF: 0.169 AC: 8947 AN: 52916

Middle Eastern (MID) AF: 0.196 AC: 1130 AN: 5756

European-Non Finnish (NFE) AF: 0.211 AC: 234256 AN: 1108258

Other (OTH) AF: 0.202 AC: 12185 AN: 60226

GnomAD4 genome AF: 0.161 AC: 24571 AN: 152196 Hom.: 2237 Cov.: 32 AF XY: 0.158 AC XY: 11768 AN XY: 74390

African (AFR) AF: 0.0743 AC: 3087 AN: 41532

American (AMR) AF: 0.144 AC: 2200 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 1053 AN: 3472

East Asian (EAS) AF: 0.174 AC: 899 AN: 5176

South Asian (SAS) AF: 0.174 AC: 839 AN: 4818

European-Finnish (FIN) AF: 0.164 AC: 1733 AN: 10596

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.206 AC: 14019 AN: 67994

Other (OTH) AF: 0.181 AC: 384 AN: 2116

Alfa AF: 0.170 Hom.: 2692

Bravo AF: 0.158

Asia WGS AF: 0.213 AC: 738 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	4.1
DANN	Benign	0.59
PhyloP100		-0.86
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2305949; hg19: chr4-55980456; COSMIC: COSV55758738;