rs1870377

Positions:

• chr4-55106807-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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 (★). 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 criteria provided, single submitter 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 -14 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 criteria_provided_single_submitter, 1 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	UniProt
KDR	NM_002253.4	c.1416A>T	p.Gln472His	missense_variant	11/30	ENST00000263923.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KDR	ENST00000263923.5	c.1416A>T	p.Gln472His	missense_variant	11/30	1	NM_002253.4	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: criteria provided, single submitter

Submissions by phenotype

KDR-related disorder Benign:1

Benign, criteria provided, single submitter

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;