4-55115364-C-T

Variant names:

• chr4-55115364-C-T
• rs35636987
• NM_002253.4:c.406G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002253.4(KDR):​c.406G>A​(p.Val136Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000478 in 1,555,858 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (5 hom.)
• Consequence: KDR NM_002253.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.13
• Publications: 12 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009088397).
• BP6: Variant 4-55115364-C-T is Benign according to our data. Variant chr4-55115364-C-T is described in ClinVar as Benign. ClinVar VariationId is 134611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 69 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.406G>A	p.Val136Met	missense	Exon 4 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.406G>A	p.Val136Met	missense	Exon 4 of 30	ENSP00000263923.4	P35968-1
	KDR	ENST00000512566.1	TSL:1	n.406G>A		non_coding_transcript_exon	Exon 4 of 13
	KDR	ENST00000922964.1		c.406G>A	p.Val136Met	missense	Exon 4 of 29	ENSP00000593023.1

Frequencies

GnomAD3 genomes AF: 0.000454 AC: 69 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0119

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000753 AC: 189 AN: 251102 AF XY: 0.000729

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00914

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.0000616

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000480 AC: 674 AN: 1403688 Hom.: 5 Cov.: 24 AF XY: 0.000477 AC XY: 335 AN XY: 702262

African (AFR) AF: 0.00 AC: 0 AN: 32274

American (AMR) AF: 0.0000448 AC: 2 AN: 44604

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25774

East Asian (EAS) AF: 0.0139 AC: 549 AN: 39376

South Asian (SAS) AF: 0.000223 AC: 19 AN: 85168

European-Finnish (FIN) AF: 0.0000937 AC: 5 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.0000378 AC: 40 AN: 1059088

Other (OTH) AF: 0.00101 AC: 59 AN: 58380

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.000511 AC XY: 38 AN XY: 74406

African (AFR) AF: 0.00 AC: 0 AN: 41528

American (AMR) AF: 0.000262 AC: 4 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0120 AC: 62 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67990

Other (OTH) AF: 0.000474 AC: 1 AN: 2110

Alfa AF: 0.000525 Hom.: 1

Bravo AF: 0.000374

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000766 AC: 93

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		1.1
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.018	D
Polyphen		0.99	D
Vest4		0.39
MVP		0.13
MPC		0.52
ClinPred		0.064	T
GERP RS		3.1
Varity_R		0.26
gMVP		0.69
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs35636987; hg19: chr4-55981531;