6-43783932-G-C

Variant names:

• chr6-43783932-G-C
• rs3025036
• ENST00000480614.1:n.9615G>C

Variant summary

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

The ENST00000480614.1(VEGFA):​n.9615G>C 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 0.717 in 159,864 control chromosomes in the GnomAD database, including 41,476 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 0.72 (39500 hom., cov: 33)
  • Exomes 𝑓: 0.71 (1976 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.203
• Publications: 5 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 = 0.88 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.1167-609G>C		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.1167-609G>C		intron_variant	Intron 7 of 7		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.717 AC: 109065 AN: 152064 Hom.: 39444 Cov.: 33

Gnomad AFR AF: 0.776

Gnomad AMI AF: 0.667

Gnomad AMR AF: 0.776

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.901

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.669

Gnomad MID AF: 0.633

Gnomad NFE AF: 0.666

Gnomad OTH AF: 0.705

GnomAD4 exome AF: 0.708 AC: 5441 AN: 7682 Hom.: 1976 Cov.: 0 AF XY: 0.708 AC XY: 2836 AN XY: 4008

African (AFR) AF: 0.653 AC: 47 AN: 72

American (AMR) AF: 0.785 AC: 1500 AN: 1910

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 12 AN: 28

East Asian (EAS) AF: 0.906 AC: 366 AN: 404

South Asian (SAS) AF: 0.712 AC: 628 AN: 882

European-Finnish (FIN) AF: 0.667 AC: 52 AN: 78

Middle Eastern (MID) AF: 0.667 AC: 4 AN: 6

European-Non Finnish (NFE) AF: 0.654 AC: 2605 AN: 3986

Other (OTH) AF: 0.718 AC: 227 AN: 316

GnomAD4 genome AF: 0.717 AC: 109182 AN: 152182 Hom.: 39500 Cov.: 33 AF XY: 0.721 AC XY: 53689 AN XY: 74420

African (AFR) AF: 0.776 AC: 32236 AN: 41520

American (AMR) AF: 0.776 AC: 11873 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.636 AC: 2207 AN: 3470

East Asian (EAS) AF: 0.901 AC: 4666 AN: 5176

South Asian (SAS) AF: 0.731 AC: 3531 AN: 4828

European-Finnish (FIN) AF: 0.669 AC: 7092 AN: 10606

Middle Eastern (MID) AF: 0.622 AC: 183 AN: 294

European-Non Finnish (NFE) AF: 0.666 AC: 45297 AN: 67974

Other (OTH) AF: 0.707 AC: 1490 AN: 2108

Alfa AF: 0.665 Hom.: 16671

Bravo AF: 0.727

Asia WGS AF: 0.790 AC: 2747 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	2.1
DANN	Benign	0.30
PhyloP100		-0.20
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: rs3025036; hg19: chr6-43751669;