Genetic Variant NM_002253.4:c.3663T>A (chr4-55082635-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002253.4(KDR):c.3663T>A(p.Ser1221Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. S1221S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

KDR
NM_002253.4 missense, splice_region

Scores

Splicing: ADA: 0.0002876

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.04

Publications

0 publications found

Variant links:

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

KDR links:

ENSG00000250646 (HGNC:58789):

ENSG00000250646 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1792714).

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.3663T>A	p.Ser1221Arg	missense splice_region	Exon 28 of 30	NP_002244.1	P35968-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KDR	ENST00000263923.5	TSL:1 MANE Select	c.3663T>A	p.Ser1221Arg	missense splice_region	Exon 28 of 30	ENSP00000263923.4	P35968-1
KDR	ENST00000922964.1		c.3321T>A	p.Ser1107Arg	missense splice_region	Exon 27 of 29	ENSP00000593023.1
KDR	ENST00000647068.1		n.3676T>A		splice_region non_coding_transcript_exon	Exon 28 of 30

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.48

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.077

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.056

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.67

M_CAP

Benign

0.020

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.81

PhyloP100

2.0

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-0.64

REVEL

Uncertain

0.33

Sift

Benign

0.10

Sift4G

Benign

0.34

Polyphen

0.044

Vest4

0.28

MutPred

0.36

Gain of MoRF binding (P = 0.0206)

MVP

0.52

MPC

0.067

ClinPred

0.53

GERP RS

4.5

Varity_R

0.27

gMVP

0.49

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00029

dbscSNV1_RF

Benign

0.026

SpliceAI score (max)

0.11

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over