4-55096165-C-T

Variant names:

• chr4-55096165-C-T
• rs17085274
• NM_002253.4:c.2728+64G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002253.4(KDR):​c.2728+64G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 881,008 control chromosomes in the GnomAD database, including 50 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 0.012 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (20 hom.)
• Consequence: KDR NM_002253.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.55
• Publications: 0 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=-0.8).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0118 (1800/152274) while in subpopulation AFR AF = 0.0416 (1727/41560). AF 95% confidence interval is 0.0399. There are 30 homozygotes in GnomAd4. There are 862 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1800 AD gene.

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.2728+64G>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.2728+64G>A		intron	N/A	ENSP00000263923.4
	KDR	ENST00000922964.1		c.2386+64G>A		intron	N/A	ENSP00000593023.1
	KDR	ENST00000509309.1	TSL:3	n.492+64G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1784 AN: 152156 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.0413

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00354

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00527

GnomAD4 exome AF: 0.00147 AC: 1071 AN: 728734 Hom.: 20 AF XY: 0.00115 AC XY: 447 AN XY: 389986

African (AFR) AF: 0.0442 AC: 866 AN: 19612

American (AMR) AF: 0.00172 AC: 74 AN: 42930

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21488

East Asian (EAS) AF: 0.00 AC: 0 AN: 36150

South Asian (SAS) AF: 0.0000424 AC: 3 AN: 70724

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43940

Middle Eastern (MID) AF: 0.00147 AC: 5 AN: 3398

European-Non Finnish (NFE) AF: 0.0000506 AC: 23 AN: 454098

Other (OTH) AF: 0.00275 AC: 100 AN: 36394

GnomAD4 genome AF: 0.0118 AC: 1800 AN: 152274 Hom.: 30 Cov.: 32 AF XY: 0.0116 AC XY: 862 AN XY: 74460

African (AFR) AF: 0.0416 AC: 1727 AN: 41560

American (AMR) AF: 0.00353 AC: 54 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68020

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.000281 Hom.: 0

Bravo AF: 0.0128

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	14
DANN	Benign	0.65
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

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: rs17085274; hg19: chr4-55962332;