KDR p.Gly539Arg

Variant names:

• chr4-55105862-C-G
• NM_002253.4:c.1615G>C
• KDR p.Gly539Arg

Your query was ambiguous. Multiple possible variants found:

• chr4-55105862-C-G
• chr4-55105862-C-T
• chr4-55105860-TCC-ACG
• chr4-55105860-TCC-GCG
• chr4-55105860-TCC-CCG
• chr4-55105860-TCC-CCT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002253.4(KDR):​c.1615G>C​(p.Gly539Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G539E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KDR NM_002253.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.16
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.219434).

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.1615G>C	p.Gly539Arg	missense	Exon 12 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.1615G>C	p.Gly539Arg	missense	Exon 12 of 30	ENSP00000263923.4	P35968-1
	KDR	ENST00000512566.1	TSL:1	n.1615G>C		non_coding_transcript_exon	Exon 12 of 13
	KDR	ENST00000922964.1		c.1615G>C	p.Gly539Arg	missense	Exon 12 of 29	ENSP00000593023.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		3.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.028
Sift	Benign	0.071	T
Sift4G	Benign	0.19	T
Varity_R		0.34
gMVP		0.63
Mutation Taster		=66/34	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

hg19: chr4-55972029;