NM_002253.4:c.3848+15T>C

Variant names:

• chr4-55081941-A-G
• rs2412617
• NM_002253.4:c.3848+15T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002253.4(KDR):​c.3848+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,579,230 control chromosomes in the GnomAD database, including 787,894 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 1.0 (75710 hom., cov: 32)
  • Exomes 𝑓: 1.0 (712184 hom.)
• Consequence: KDR NM_002253.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.0530
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-55081941-A-G is Benign according to our data. Variant chr4-55081941-A-G is described in ClinVar as Benign. ClinVar VariationId is 518355.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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.3848+15T>C		intron	N/A	NP_002244.1	P35968-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDR	ENST00000263923.5	TSL:1 MANE Select	c.3848+15T>C		intron	N/A	ENSP00000263923.4	P35968-1
	KDR	ENST00000922964.1		c.3506+15T>C		intron	N/A	ENSP00000593023.1
	ENSG00000250646	ENST00000511222.1	TSL:5	n.233+6699A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.997 AC: 151765 AN: 152228 Hom.: 75651 Cov.: 32

Gnomad AFR AF: 0.992

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.997

Gnomad ASJ AF: 0.995

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.997

GnomAD2 exomes AF: 0.999 AC: 250551 AN: 250914 AF XY: 0.999

Gnomad AFR exome AF: 0.992

Gnomad AMR exome AF: 0.997

Gnomad ASJ exome AF: 0.995

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.996

GnomAD4 exome AF: 0.999 AC: 1425623 AN: 1426884 Hom.: 712184 Cov.: 25 AF XY: 0.999 AC XY: 711743 AN XY: 712348

African (AFR) AF: 0.992 AC: 32478 AN: 32756

American (AMR) AF: 0.997 AC: 44558 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 25770 AN: 25872

East Asian (EAS) AF: 1.00 AC: 39536 AN: 39536

South Asian (SAS) AF: 1.00 AC: 85471 AN: 85474

European-Finnish (FIN) AF: 1.00 AC: 53388 AN: 53388

Middle Eastern (MID) AF: 0.995 AC: 5654 AN: 5684

European-Non Finnish (NFE) AF: 0.999 AC: 1079684 AN: 1080294

Other (OTH) AF: 0.998 AC: 59084 AN: 59198

GnomAD4 genome AF: 0.997 AC: 151883 AN: 152346 Hom.: 75710 Cov.: 32 AF XY: 0.997 AC XY: 74276 AN XY: 74498

African (AFR) AF: 0.992 AC: 41231 AN: 41578

American (AMR) AF: 0.997 AC: 15258 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.995 AC: 3456 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5186 AN: 5186

South Asian (SAS) AF: 1.00 AC: 4828 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10616 AN: 10616

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67994 AN: 68042

Other (OTH) AF: 0.997 AC: 2110 AN: 2116

Alfa AF: 0.998 Hom.: 13910

Bravo AF: 0.996

Asia WGS AF: 1.00 AC: 3473 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Capillary infantile hemangioma (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.2
DANN	Benign	0.63
PhyloP100		-0.053
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: rs2412617; hg19: chr4-55948108;