4-55113391-C-T

Variant names:

• chr4-55113391-C-T
• rs2305948
• NM_002253.4:c.889G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002253.4(KDR):​c.889G>A​(p.Val297Ile) variant causes a missense change. The variant allele was found at a frequency of 0.105 in 1,613,886 control chromosomes in the GnomAD database, including 9,959 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.14 (1762 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8197 hom.)
• Consequence: KDR NM_002253.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: 4.92
• Publications: 240 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017504394).
• BP6: Variant 4-55113391-C-T is Benign according to our data. Variant chr4-55113391-C-T is described in ClinVar as Benign. ClinVar VariationId is 134616.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDR	NM_002253.4	MANE Select	c.889G>A	p.Val297Ile	missense	Exon 7 of 30	NP_002244.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KDR	ENST00000263923.5	TSL:1 MANE Select	c.889G>A	p.Val297Ile	missense	Exon 7 of 30	ENSP00000263923.4
	KDR	ENST00000512566.1	TSL:1	n.889G>A		non_coding_transcript_exon	Exon 7 of 13
	KDR	ENST00000922964.1		c.889G>A	p.Val297Ile	missense	Exon 7 of 29	ENSP00000593023.1

Frequencies

GnomAD3 genomes AF: 0.138 AC: 20918 AN: 152026 Hom.: 1757 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.0789

Gnomad AMR AF: 0.0910

Gnomad ASJ AF: 0.0994

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.0865

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0995

Gnomad OTH AF: 0.122

GnomAD2 exomes AF: 0.106 AC: 26587 AN: 251324 AF XY: 0.105

Gnomad AFR exome AF: 0.235

Gnomad AMR exome AF: 0.0604

Gnomad ASJ exome AF: 0.105

Gnomad EAS exome AF: 0.145

Gnomad FIN exome AF: 0.0883

Gnomad NFE exome AF: 0.0979

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.102 AC: 148422 AN: 1461742 Hom.: 8197 Cov.: 32 AF XY: 0.101 AC XY: 73567 AN XY: 727174

African (AFR) AF: 0.239 AC: 8011 AN: 33474

American (AMR) AF: 0.0631 AC: 2821 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0994 AC: 2598 AN: 26128

East Asian (EAS) AF: 0.127 AC: 5039 AN: 39692

South Asian (SAS) AF: 0.103 AC: 8909 AN: 86258

European-Finnish (FIN) AF: 0.0891 AC: 4761 AN: 53418

Middle Eastern (MID) AF: 0.101 AC: 583 AN: 5766

European-Non Finnish (NFE) AF: 0.0980 AC: 109001 AN: 1111904

Other (OTH) AF: 0.111 AC: 6699 AN: 60392

GnomAD4 genome AF: 0.138 AC: 20945 AN: 152144 Hom.: 1762 Cov.: 32 AF XY: 0.135 AC XY: 10061 AN XY: 74376

African (AFR) AF: 0.239 AC: 9920 AN: 41476

American (AMR) AF: 0.0910 AC: 1391 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0994 AC: 345 AN: 3470

East Asian (EAS) AF: 0.143 AC: 738 AN: 5176

South Asian (SAS) AF: 0.104 AC: 499 AN: 4818

European-Finnish (FIN) AF: 0.0865 AC: 916 AN: 10588

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0995 AC: 6765 AN: 68012

Other (OTH) AF: 0.123 AC: 259 AN: 2110

Alfa AF: 0.111 Hom.: 4787

Bravo AF: 0.141

TwinsUK AF: 0.104 AC: 384

ALSPAC AF: 0.101 AC: 389

ESP6500AA AF: 0.223 AC: 984

ESP6500EA AF: 0.101 AC: 872

ExAC AF: 0.109 AC: 13217

Asia WGS AF: 0.158 AC: 549 AN: 3478

EpiCase AF: 0.0996

EpiControl AF: 0.0961

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	KDR-related disorder (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.9
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.16
Sift	Benign	0.059	T
Sift4G	Uncertain	0.052	T
Polyphen		1.0	D
Vest4		0.11
MPC		0.61
ClinPred		0.033	T
GERP RS		4.6
Varity_R		0.58
gMVP		0.77
Mutation Taster		=84/16	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2305948; hg19: chr4-55979558; COSMIC: COSV55758732;