4-55081978-T-C

Variant names:

• chr4-55081978-T-C
• NM_002253.4:c.3826A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_002253.4(KDR):​c.3826A>G​(p.Thr1276Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KDR NM_002253.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.458

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]

ENSG00000250646 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0351761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KDR	NM_002253.4	c.3826A>G	p.Thr1276Ala	missense_variant	Exon 29 of 30	ENST00000263923.5	NP_002244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KDR	ENST00000263923.5	c.3826A>G	p.Thr1276Ala	missense_variant	Exon 29 of 30	1	NM_002253.4	ENSP00000263923.4
KDR	ENST00000647068.1	n.3839A>G		non_coding_transcript_exon_variant	Exon 29 of 30
ENSG00000250646	ENST00000511222.1	n.233+6736T>C		intron_variant	Intron 3 of 3	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461014 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726876

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Benign	0.074	T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.53	.;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.035	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.14	N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.12	.;N
REVEL	Benign	0.16
Sift	Benign	0.87	.;T
Sift4G	Benign	0.75	.;T
Polyphen		0.0	B;B
Vest4		0.11
MutPred		0.12		Loss of phosphorylation at T1276 (P = 0.035);Loss of phosphorylation at T1276 (P = 0.035);
MVP		0.093
MPC		0.058
ClinPred		0.056	T
GERP RS		2.9
Varity_R		0.070
gMVP		0.16

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-55948145; COSMIC: COSV55778558;