rs56286620

chr4-55107765-A-Cchr4-55107765-A-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002253.4(KDR):c.1384T>G(p.Leu462Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00187 in 1,613,950 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (6 hom.)
• Consequence: KDR NM_002253.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:2 O:1
• Conservation: PhyloP100: 0.293

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004890412).
• BP6: Variant 4-55107765-A-C is Benign according to our data. Variant chr4-55107765-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 134602.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 255 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KDR	NM_002253.4	c.1384T>G	p.Leu462Val	missense_variant	10/30	ENST00000263923.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDR	ENST00000263923.5	c.1384T>G	p.Leu462Val	missense_variant	10/30	1	NM_002253.4	P1
KDR	ENST00000512566.1	n.1384T>G		non_coding_transcript_exon_variant	10/13	1
KDR	ENST00000647068.1	n.1397T>G		non_coding_transcript_exon_variant	10/30

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 255 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00149 AC: 373 AN: 251080 Hom.: 1 AF XY: 0.00148 AC XY: 201 AN XY: 135708

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00615

Gnomad NFE exome AF: 0.00189

Gnomad OTH exome AF: 0.000981

GnomAD4 exome AF: 0.00189 AC: 2767 AN: 1461672 Hom.: 6 Cov.: 32 AF XY: 0.00189 AC XY: 1375 AN XY: 727150

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00504

Gnomad4 NFE exome AF: 0.00217

Gnomad4 OTH exome AF: 0.000944

GnomAD4 genome AF: 0.00167 AC: 255 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00179 AC XY: 133 AN XY: 74446

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00641

Gnomad4 NFE AF: 0.00216

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00186 Hom.: 0

Bravo AF: 0.00124

ExAC AF: 0.00135 AC: 164

EpiCase AF: 0.00147

EpiControl AF: 0.00107

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	KDR: BP4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The KDR p.Leu462Val variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs56286620) and ClinVar (submitted by ITMI with no classification). The variant was identified in control databases in 420 of 282462 chromosomes (1 homozygous) at a frequency of 0.001487 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Finnish) in 151 of 25100 chromosomes (freq: 0.006016), European (non-Finnish) in 240 of 128880 chromosomes (freq: 0.001862), Other in 7 of 7206 chromosomes (freq: 0.000971), African in 15 of 24956 chromosomes (freq: 0.000601) and Latino in 7 of 35406 chromosomes (freq: 0.000198), but was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Leu462 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.072	T;T
Eigen	Benign	-0.048
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.91	D
MetaRNN	Benign	0.0049	T;T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.4	M;M
MutationTaster	Benign	0.76	D
PrimateAI	Benign	0.30	T
Polyphen		0.86	P;P
Vest4		0.51
MVP		0.33
MPC		0.42
ClinPred		0.037	T
GERP RS		-0.73
Varity_R		0.18
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs56286620; hg19: chr4-55973932;