4-55114137-G-C

Variant names:

• chr4-55114137-G-C
• rs587778429
• NM_002253.4:c.787C>G
• KDR p.Pro263Ala

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_002253.4(KDR):​c.787C>G​(p.Pro263Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,704 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P263S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: KDR NM_002253.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.23
• Publications: 5 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: Likely_benign. The variant received -1 ACMG points.

• BS2: High AC in GnomAdExome4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.787C>G	p.Pro263Ala	missense	Exon 6 of 30	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.787C>G	p.Pro263Ala	missense	Exon 6 of 30	ENSP00000263923.4	P35968-1
	KDR	ENST00000512566.1	TSL:1	n.787C>G		non_coding_transcript_exon	Exon 6 of 13
	KDR	ENST00000922964.1		c.787C>G	p.Pro263Ala	missense	Exon 6 of 29	ENSP00000593023.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000159 AC: 4 AN: 251404 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461704 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 727152

African (AFR) AF: 0.0000598 AC: 2 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111890

Other (OTH) AF: 0.0000166 AC: 1 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000192 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		5.2
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Benign	0.25
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.017	D
Varity_R		0.83
gMVP		0.78
Mutation Taster		=93/7	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587778429;

hg19: chr4-55980304;

COSMIC: COSV55773224;