4-55094992-T-C

Variant names:

• chr4-55094992-T-C
• rs2219471
• NM_002253.4:c.2818-37A>G

Variant summary

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

The ENST00000263923.5(KDR):​c.2818-37A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,600,124 control chromosomes in the GnomAD database, including 46,516 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 0.22 (3938 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42578 hom.)
• Consequence: KDR ENST00000263923.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.512
• Publications: 25 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=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000263923.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDR	NM_002253.4	MANE Select	c.2818-37A>G		intron	N/A	NP_002244.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDR	ENST00000263923.5	TSL:1 MANE Select	c.2818-37A>G		intron	N/A	ENSP00000263923.4
	KDR	ENST00000509309.1	TSL:3	n.582-37A>G		intron	N/A
	KDR	ENST00000647068.1		n.2831-37A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32907 AN: 152016 Hom.: 3931 Cov.: 32

Gnomad AFR AF: 0.140

Gnomad AMI AF: 0.397

Gnomad AMR AF: 0.152

Gnomad ASJ AF: 0.202

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.247

Gnomad OTH AF: 0.209

GnomAD2 exomes AF: 0.225 AC: 56006 AN: 249140 AF XY: 0.226

Gnomad AFR exome AF: 0.137

Gnomad AMR exome AF: 0.100

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.473

Gnomad FIN exome AF: 0.307

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.217

GnomAD4 exome AF: 0.236 AC: 341504 AN: 1447990 Hom.: 42578 Cov.: 27 AF XY: 0.234 AC XY: 169126 AN XY: 721336

African (AFR) AF: 0.137 AC: 4552 AN: 33174

American (AMR) AF: 0.106 AC: 4710 AN: 44640

Ashkenazi Jewish (ASJ) AF: 0.200 AC: 5211 AN: 26034

East Asian (EAS) AF: 0.436 AC: 17274 AN: 39594

South Asian (SAS) AF: 0.143 AC: 12308 AN: 85890

European-Finnish (FIN) AF: 0.293 AC: 15589 AN: 53282

Middle Eastern (MID) AF: 0.181 AC: 1039 AN: 5750

European-Non Finnish (NFE) AF: 0.243 AC: 266913 AN: 1099756

Other (OTH) AF: 0.232 AC: 13908 AN: 59870

GnomAD4 genome AF: 0.217 AC: 32941 AN: 152134 Hom.: 3938 Cov.: 32 AF XY: 0.219 AC XY: 16289 AN XY: 74368

African (AFR) AF: 0.140 AC: 5830 AN: 41528

American (AMR) AF: 0.152 AC: 2319 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.202 AC: 700 AN: 3470

East Asian (EAS) AF: 0.463 AC: 2392 AN: 5162

South Asian (SAS) AF: 0.149 AC: 717 AN: 4826

European-Finnish (FIN) AF: 0.317 AC: 3357 AN: 10576

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.247 AC: 16754 AN: 67966

Other (OTH) AF: 0.216 AC: 456 AN: 2108

Alfa AF: 0.228 Hom.: 8685

Bravo AF: 0.201

Asia WGS AF: 0.305 AC: 1059 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.62
DANN	Benign	0.23
PhyloP100		-0.51
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2219471; hg19: chr4-55961159; COSMIC: COSV55764437; COSMIC: COSV55764437;