chr4-55105862-C-T

Position:

• chr4-55105862-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002253.4(KDR):​c.1615G>A​(p.Gly539Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00254 in 1,612,952 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0015 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0026 (5 hom.)
• Consequence: KDR NM_002253.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3 O:1
• Conservation: PhyloP100: 3.16

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013275832).
• BP6: Variant 4-55105862-C-T is Benign according to our data. Variant chr4-55105862-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 134605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 234 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KDR	NM_002253.4	c.1615G>A	p.Gly539Arg	missense_variant	12/30	ENST00000263923.5	NP_002244.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KDR	ENST00000263923.5	c.1615G>A	p.Gly539Arg	missense_variant	12/30	1	NM_002253.4	ENSP00000263923	P1
KDR	ENST00000512566.1	n.1615G>A		non_coding_transcript_exon_variant	12/13	1
KDR	ENST00000647068.1	n.1628G>A		non_coding_transcript_exon_variant	12/30

Frequencies

GnomAD3 genomes AF: 0.00154 AC: 234 AN: 152198 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00287

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00151 AC: 379 AN: 251334 Hom.: 1 AF XY: 0.00149 AC XY: 202 AN XY: 135828

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00282

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00264 AC: 3863 AN: 1460636 Hom.: 5 Cov.: 30 AF XY: 0.00256 AC XY: 1860 AN XY: 726736

Gnomad4 AFR exome AF: 0.000509

Gnomad4 AMR exome AF: 0.000760

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00320

Gnomad4 OTH exome AF: 0.00295

GnomAD4 genome AF: 0.00154 AC: 234 AN: 152316 Hom.: 1 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74484

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00287

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00224 Hom.: 1

Bravo AF: 0.00158

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.00161 AC: 195

EpiCase AF: 0.00251

EpiControl AF: 0.00279

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The KDR p.G539R variant was identified in the literature, however the frequency of this variant in an affected population was not provided. The p.G539 variant was identified in control databases in 426 of 282734 chromosomes (1 homozygous) at a frequency of 0.001507 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 362 of 129064 chromosomes (freq: 0.002805), Other in 15 of 7218 chromosomes (freq: 0.002078), Latino in 23 of 35438 chromosomes (freq: 0.000649), South Asian in 10 of 30616 chromosomes (freq: 0.000327), African in 8 of 24958 chromosomes (freq: 0.000321), European (Finnish) in 6 of 25124 chromosomes (freq: 0.000239) and Ashkenazi Jewish in 2 of 10364 chromosomes (freq: 0.000193); it was not observed in the East Asian population. The variant was also identified in dbSNP (ID: rs55716939), ClinVar (one submission from ITMI in 2017, not classified) and Cosmic (confirmed somatically in stomach tissue—adenocarcinoma). The p.G539R variant was identified at an allele frequency of 0.0007 in a cohort of 681 healthy adults and 0.0015 among those of European descent (Bodian_2014_PMID: 24728327). The p.G539R variant was identified in liver tissue of a female with cancer of unknown primary origin, though it was not found to be a driver mutation (Pannuti_2018_PMID: 29570743). In an analysis of normal and tumor tissue from 210 cancers, p.G539R was identified twice in germline (Greenman_2007_PMID: 17344846). The p.G539R variant was also identified in the Geno2MP database in 33 individuals affected with a broad range of disorders and 24 relatives of affected individuals. The p.G539R variant lies within the Ig-like C2-type domain 5 of the KDR protein and one functional study found that p.G539R demonstrated greater activity than the WT counterpart (Egan_2017_PMID: 30761385). The p.G538R variant is predicted to lead to gain of KDR protein function and may play a role in oncogenesis (Egan_2017_PMID: 30761385). The p.Gly539 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	KDR: BP4, BS1 -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.097	T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.073
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.013	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	0.66	D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	.;N
REVEL	Benign	0.027
Sift	Benign	0.071	.;T
Sift4G	Benign	0.19	.;T
Polyphen		0.0010	B;B
Vest4		0.33
MutPred		0.40		Gain of MoRF binding (P = 0.0252);Gain of MoRF binding (P = 0.0252);
MVP		0.068
MPC		0.21
ClinPred		0.020	T
GERP RS		4.5
Varity_R		0.34
gMVP		0.63

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

LitVar

Other links and lift over

dbSNP: rs55716939; hg19: chr4-55972029; COSMIC: COSV55766446;