ENST00000480614.1:n.8497C>G

Variant names:

• chr6-43782814-C-G
• rs3025028
• ENST00000480614.1:n.8497C>G

Variant summary

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

The ENST00000480614.1(VEGFA):​n.8497C>G 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 0.598 in 153,924 control chromosomes in the GnomAD database, including 27,976 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 0.60 (27604 hom., cov: 30)
  • Exomes 𝑓: 0.55 (372 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 12 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.738 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.1166+727C>G		intron_variant	Intron 7 of 7	ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.1166+727C>G		intron_variant	Intron 7 of 7		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.599 AC: 90776 AN: 151594 Hom.: 27567 Cov.: 30

Gnomad AFR AF: 0.649

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.696

Gnomad ASJ AF: 0.563

Gnomad EAS AF: 0.757

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.523

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.551

Gnomad OTH AF: 0.598

GnomAD4 exome AF: 0.555 AC: 1226 AN: 2210 Hom.: 372 Cov.: 0 AF XY: 0.564 AC XY: 630 AN XY: 1118

African (AFR) AF: 0.188 AC: 3 AN: 16

American (AMR) AF: 0.742 AC: 242 AN: 326

Ashkenazi Jewish (ASJ) AF: 0.688 AC: 11 AN: 16

East Asian (EAS) AF: 0.848 AC: 39 AN: 46

South Asian (SAS) AF: 0.640 AC: 73 AN: 114

European-Finnish (FIN) AF: 0.464 AC: 26 AN: 56

Middle Eastern (MID) AF: 0.700 AC: 7 AN: 10

European-Non Finnish (NFE) AF: 0.507 AC: 775 AN: 1530

Other (OTH) AF: 0.521 AC: 50 AN: 96

GnomAD4 genome AF: 0.599 AC: 90862 AN: 151714 Hom.: 27604 Cov.: 30 AF XY: 0.602 AC XY: 44606 AN XY: 74126

African (AFR) AF: 0.649 AC: 26823 AN: 41358

American (AMR) AF: 0.696 AC: 10616 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.563 AC: 1953 AN: 3472

East Asian (EAS) AF: 0.758 AC: 3878 AN: 5118

South Asian (SAS) AF: 0.582 AC: 2800 AN: 4808

European-Finnish (FIN) AF: 0.523 AC: 5512 AN: 10530

Middle Eastern (MID) AF: 0.554 AC: 163 AN: 294

European-Non Finnish (NFE) AF: 0.551 AC: 37367 AN: 67872

Other (OTH) AF: 0.596 AC: 1256 AN: 2108

Alfa AF: 0.586 Hom.: 3258

Bravo AF: 0.617

Asia WGS AF: 0.644 AC: 2239 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.26
DANN	Benign	0.68
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs3025028; hg19: chr6-43750551;