4-55080187-G-T

Variant names:

• chr4-55080187-G-T
• rs10006115
• NM_002253.4:c.3849-24C>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.3849-24C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0438 in 1,603,004 control chromosomes in the GnomAD database, including 1,911 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 0.055 (284 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1627 hom.)
• Consequence: KDR NM_002253.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.47
• 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

ENSG00000250646 (HGNC:58789):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.085 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.3849-24C>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.3849-24C>A		intron	N/A	ENSP00000263923.4
	KDR	ENST00000922964.1		c.3507-24C>A		intron	N/A	ENSP00000593023.1
	ENSG00000250646	ENST00000511222.1	TSL:5	n.233+4945G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0549 AC: 8350 AN: 152150 Hom.: 284 Cov.: 33

Gnomad AFR AF: 0.0829

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0302

Gnomad ASJ AF: 0.0605

Gnomad EAS AF: 0.0920

Gnomad SAS AF: 0.0877

Gnomad FIN AF: 0.0399

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0407

Gnomad OTH AF: 0.0540

GnomAD2 exomes AF: 0.0499 AC: 12514 AN: 250582 AF XY: 0.0523

Gnomad AFR exome AF: 0.0825

Gnomad AMR exome AF: 0.0240

Gnomad ASJ exome AF: 0.0618

Gnomad EAS exome AF: 0.0978

Gnomad FIN exome AF: 0.0358

Gnomad NFE exome AF: 0.0385

Gnomad OTH exome AF: 0.0476

GnomAD4 exome AF: 0.0426 AC: 61849 AN: 1450736 Hom.: 1627 Cov.: 30 AF XY: 0.0443 AC XY: 31974 AN XY: 722398

African (AFR) AF: 0.0886 AC: 2942 AN: 33214

American (AMR) AF: 0.0258 AC: 1154 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0621 AC: 1620 AN: 26078

East Asian (EAS) AF: 0.0833 AC: 3304 AN: 39668

South Asian (SAS) AF: 0.0845 AC: 7268 AN: 86000

European-Finnish (FIN) AF: 0.0367 AC: 1955 AN: 53260

Middle Eastern (MID) AF: 0.0782 AC: 342 AN: 4376

European-Non Finnish (NFE) AF: 0.0364 AC: 40214 AN: 1103540

Other (OTH) AF: 0.0509 AC: 3050 AN: 59894

GnomAD4 genome AF: 0.0550 AC: 8374 AN: 152268 Hom.: 284 Cov.: 33 AF XY: 0.0556 AC XY: 4137 AN XY: 74458

African (AFR) AF: 0.0834 AC: 3462 AN: 41532

American (AMR) AF: 0.0301 AC: 461 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0605 AC: 210 AN: 3472

East Asian (EAS) AF: 0.0919 AC: 476 AN: 5182

South Asian (SAS) AF: 0.0879 AC: 424 AN: 4822

European-Finnish (FIN) AF: 0.0399 AC: 424 AN: 10616

Middle Eastern (MID) AF: 0.109 AC: 32 AN: 294

European-Non Finnish (NFE) AF: 0.0406 AC: 2765 AN: 68024

Other (OTH) AF: 0.0539 AC: 114 AN: 2116

Alfa AF: 0.0447 Hom.: 82

Bravo AF: 0.0541

Asia WGS AF: 0.0900 AC: 312 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.9
DANN	Benign	0.60
PhyloP100		1.5
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: rs10006115; hg19: chr4-55946354; COSMIC: COSV55768451;