rs1870377

Positions:

• chr4-55106807-T-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002253.4(KDR):​c.1416A>T​(p.Gln472His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.227 in 1,599,452 control chromosomes in the GnomAD database, including 44,436 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.20 (3613 hom., cov: 33)
  • Exomes 𝑓: 0.23 (40823 hom.)
• Consequence: KDR NM_002253.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: -0.0390

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.7933717E-4).
• BP6: Variant 4-55106807-T-A is Benign according to our data. Variant chr4-55106807-T-A is described in ClinVar as [Benign]. Clinvar id is 134603.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr4-55106807-T-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDR	NM_002253.4	c.1416A>T	p.Gln472His	missense_variant	11/30	ENST00000263923.5	NP_002244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDR	ENST00000263923.5	c.1416A>T	p.Gln472His	missense_variant	11/30	1	NM_002253.4	ENSP00000263923	P1
KDR	ENST00000512566.1	n.1416A>T		non_coding_transcript_exon_variant	11/13	1
KDR	ENST00000647068.1	n.1429A>T		non_coding_transcript_exon_variant	11/30

Frequencies

GnomAD3 genomes AF: 0.204 AC: 30976 AN: 152078 Hom.: 3610 Cov.: 33

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.245

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.201

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.303

Gnomad MID AF: 0.161

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.201

GnomAD3 exomes AF: 0.223 AC: 55838 AN: 250700 Hom.: 7417 AF XY: 0.225 AC XY: 30538 AN XY: 135550

Gnomad AFR exome AF: 0.103

Gnomad AMR exome AF: 0.102

Gnomad ASJ exome AF: 0.197

Gnomad EAS exome AF: 0.479

Gnomad SAS exome AF: 0.164

Gnomad FIN exome AF: 0.298

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.230 AC: 332586 AN: 1447256 Hom.: 40823 Cov.: 29 AF XY: 0.230 AC XY: 165501 AN XY: 720958

Gnomad4 AFR exome AF: 0.102

Gnomad4 AMR exome AF: 0.107

Gnomad4 ASJ exome AF: 0.202

Gnomad4 EAS exome AF: 0.435

Gnomad4 SAS exome AF: 0.164

Gnomad4 FIN exome AF: 0.284

Gnomad4 NFE exome AF: 0.235

Gnomad4 OTH exome AF: 0.228

GnomAD4 genome AF: 0.204 AC: 30991 AN: 152196 Hom.: 3613 Cov.: 33 AF XY: 0.207 AC XY: 15364 AN XY: 74388

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.149

Gnomad4 ASJ AF: 0.201

Gnomad4 EAS AF: 0.467

Gnomad4 SAS AF: 0.169

Gnomad4 FIN AF: 0.303

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.206

Alfa AF: 0.240 Hom.: 3513

Bravo AF: 0.188

TwinsUK AF: 0.237 AC: 878

ALSPAC AF: 0.242 AC: 931

ESP6500AA AF: 0.110 AC: 485

ESP6500EA AF: 0.237 AC: 2037

ExAC AF: 0.219 AC: 26633

Asia WGS AF: 0.317 AC: 1101 AN: 3478

EpiCase AF: 0.240

EpiControl AF: 0.239

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

KDR-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 02, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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	0.077
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	1.8
DANN	Benign	0.73
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.068	N
LIST_S2	Benign	0.36	.;T
MetaRNN	Benign	0.00028	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;L
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	.;N
REVEL	Benign	0.17
Sift	Benign	0.033	.;D
Sift4G	Uncertain	0.027	.;D
Polyphen		0.0030	B;B
Vest4		0.034
MutPred		0.22		Loss of sheet (P = 0.0181);Loss of sheet (P = 0.0181);
MPC		0.15
ClinPred		0.0095	T
GERP RS		-1.8
Varity_R		0.029
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs1870377; hg19: chr4-55972974; COSMIC: COSV55758724;