rs3025015

Variant names:

• chr6-43780613-G-A
• rs3025015
• ENST00000480614.1:n.6296G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000480614.1(VEGFA):​n.6296G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0506 in 1,459,574 control chromosomes in the GnomAD database, including 2,180 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.044 (194 hom., cov: 33)
  • Exomes 𝑓: 0.051 (1986 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.882
• Publications: 9 publications found

Genes affected

VEGFA (HGNC:12680): (vascular endothelial growth factor A) This gene is a member of the PDGF/VEGF growth factor family. It encodes a heparin-binding protein, which exists as a disulfide-linked homodimer. This growth factor induces proliferation and migration of vascular endothelial cells, and is essential for both physiological and pathological angiogenesis. Disruption of this gene in mice resulted in abnormal embryonic blood vessel formation. This gene is upregulated in many known tumors and its expression is correlated with tumor stage and progression. Elevated levels of this protein are found in patients with POEMS syndrome, also known as Crow-Fukase syndrome. Allelic variants of this gene have been associated with microvascular complications of diabetes 1 (MVCD1) and atherosclerosis. Alternatively spliced transcript variants encoding different isoforms have been described. There is also evidence for alternative translation initiation from upstream non-AUG (CUG) codons resulting in additional isoforms. A recent study showed that a C-terminally extended isoform is produced by use of an alternative in-frame translation termination codon via a stop codon readthrough mechanism, and that this isoform is antiangiogenic. Expression of some isoforms derived from the AUG start codon is regulated by a small upstream open reading frame, which is located within an internal ribosome entry site. The levels of VEGF are increased during infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), thus promoting inflammation by facilitating recruitment of inflammatory cells, and by increasing the level of angiopoietin II (Ang II), one of two products of the SARS-CoV-2 binding target, angiotensin-converting enzyme 2 (ACE2). In turn, Ang II facilitates the elevation of VEGF, thus forming a vicious cycle in the release of inflammatory cytokines. [provided by RefSeq, Jun 2020]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.074 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.963-119G>A		intron_variant	Intron 5 of 7	ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.963-119G>A		intron_variant	Intron 5 of 7		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.0438 AC: 6656 AN: 152102 Hom.: 193 Cov.: 33

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0367

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0802

Gnomad SAS AF: 0.0629

Gnomad FIN AF: 0.0719

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0555

Gnomad OTH AF: 0.0377

GnomAD4 exome AF: 0.0513 AC: 67118 AN: 1307354 Hom.: 1986 Cov.: 19 AF XY: 0.0516 AC XY: 33620 AN XY: 651816

African (AFR) AF: 0.0131 AC: 397 AN: 30336

American (AMR) AF: 0.0236 AC: 886 AN: 37532

Ashkenazi Jewish (ASJ) AF: 0.0155 AC: 380 AN: 24542

East Asian (EAS) AF: 0.0417 AC: 1531 AN: 36720

South Asian (SAS) AF: 0.0579 AC: 4615 AN: 79712

European-Finnish (FIN) AF: 0.0662 AC: 2793 AN: 42208

Middle Eastern (MID) AF: 0.00971 AC: 39 AN: 4016

European-Non Finnish (NFE) AF: 0.0541 AC: 53958 AN: 997168

Other (OTH) AF: 0.0457 AC: 2519 AN: 55120

GnomAD4 genome AF: 0.0438 AC: 6664 AN: 152220 Hom.: 194 Cov.: 33 AF XY: 0.0444 AC XY: 3305 AN XY: 74412

African (AFR) AF: 0.0165 AC: 685 AN: 41546

American (AMR) AF: 0.0368 AC: 562 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0161 AC: 56 AN: 3472

East Asian (EAS) AF: 0.0804 AC: 416 AN: 5176

South Asian (SAS) AF: 0.0627 AC: 302 AN: 4814

European-Finnish (FIN) AF: 0.0719 AC: 762 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0555 AC: 3777 AN: 68004

Other (OTH) AF: 0.0406 AC: 86 AN: 2116

Alfa AF: 0.0485 Hom.: 436

Bravo AF: 0.0384

Asia WGS AF: 0.0690 AC: 238 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.6
DANN	Benign	0.65
PhyloP100		-0.88
Mutation Taster		=100/0	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: rs3025015; hg19: chr6-43748350; COSMIC: COSV107217559; COSMIC: COSV107217559;