NM_002253.4:c.1444T>C

Variant names:

• chr4-55106779-A-G
• rs34231037
• NM_002253.4:c.1444T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP3 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002253.4(KDR):​c.1444T>C​(p.Cys482Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0277 in 1,602,386 control chromosomes in the GnomAD database, including 676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C482G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.022 (58 hom., cov: 32)
  • Exomes 𝑓: 0.028 (618 hom.)
• Consequence: KDR NM_002253.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4 O:2
• Conservation: PhyloP100: 6.38
• Publications: 64 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 -19 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.009061545).
• BP6: Variant 4-55106779-A-G is Benign according to our data. Variant chr4-55106779-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 12318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0223 (3397/152314) while in subpopulation NFE AF = 0.032 (2174/68026). AF 95% confidence interval is 0.0308. There are 58 homozygotes in GnomAd4. There are 1664 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3397 AD gene.

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.1444T>C	p.Cys482Arg	missense	Exon 11 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.1444T>C	p.Cys482Arg	missense	Exon 11 of 30	ENSP00000263923.4	P35968-1
	KDR	ENST00000512566.1	TSL:1	n.1444T>C		non_coding_transcript_exon	Exon 11 of 13
	KDR	ENST00000922964.1		c.1444T>C	p.Cys482Arg	missense	Exon 11 of 29	ENSP00000593023.1

Frequencies

GnomAD3 genomes AF: 0.0223 AC: 3398 AN: 152196 Hom.: 58 Cov.: 32

Gnomad AFR AF: 0.00577

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0133

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00724

Gnomad FIN AF: 0.0483

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0320

Gnomad OTH AF: 0.0249

GnomAD2 exomes AF: 0.0230 AC: 5765 AN: 250884 AF XY: 0.0236

Gnomad AFR exome AF: 0.00555

Gnomad AMR exome AF: 0.0137

Gnomad ASJ exome AF: 0.0170

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0487

Gnomad NFE exome AF: 0.0318

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0283 AC: 40966 AN: 1450072 Hom.: 618 Cov.: 28 AF XY: 0.0278 AC XY: 20106 AN XY: 722286

African (AFR) AF: 0.00504 AC: 168 AN: 33304

American (AMR) AF: 0.0139 AC: 620 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 470 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39592

South Asian (SAS) AF: 0.00743 AC: 640 AN: 86084

European-Finnish (FIN) AF: 0.0409 AC: 2183 AN: 53400

Middle Eastern (MID) AF: 0.0353 AC: 203 AN: 5744

European-Non Finnish (NFE) AF: 0.0319 AC: 35132 AN: 1101158

Other (OTH) AF: 0.0258 AC: 1550 AN: 60030

GnomAD4 genome AF: 0.0223 AC: 3397 AN: 152314 Hom.: 58 Cov.: 32 AF XY: 0.0223 AC XY: 1664 AN XY: 74470

African (AFR) AF: 0.00575 AC: 239 AN: 41568

American (AMR) AF: 0.0133 AC: 204 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0181 AC: 63 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00704 AC: 34 AN: 4832

European-Finnish (FIN) AF: 0.0483 AC: 513 AN: 10618

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0320 AC: 2174 AN: 68026

Other (OTH) AF: 0.0246 AC: 52 AN: 2114

Alfa AF: 0.0264 Hom.: 120

Bravo AF: 0.0193

TwinsUK AF: 0.0351 AC: 130

ALSPAC AF: 0.0327 AC: 126

ESP6500AA AF: 0.00522 AC: 23

ESP6500EA AF: 0.0281 AC: 242

ExAC AF: 0.0223 AC: 2705

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0326

EpiControl AF: 0.0321

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Capillary infantile hemangioma (2)
-	-	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0091	T
MetaSVM	Uncertain	-0.049	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		6.4
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.29
MPC		0.90
ClinPred		0.026	T
GERP RS		5.7
Varity_R		0.84
gMVP		0.90
Mutation Taster		=32/68	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: rs34231037; hg19: chr4-55972946; COSMIC: COSV55778415;