rs3025017

Variant names:

• chr6-43780620-G-A
• rs3025017
• ENST00000480614.1:n.6303G>A

Variant summary

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

The ENST00000480614.1(VEGFA):​n.6303G>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 0.0681 in 1,484,314 control chromosomes in the GnomAD database, including 3,886 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 0.056 (267 hom., cov: 33)
  • Exomes 𝑓: 0.070 (3619 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.319
• Publications: 6 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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0946 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.963-112G>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.963-112G>A		intron_variant	Intron 5 of 7		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.0560 AC: 8517 AN: 152112 Hom.: 267 Cov.: 33

Gnomad AFR AF: 0.0186

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0410

Gnomad ASJ AF: 0.0415

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.0871

Gnomad FIN AF: 0.0743

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0740

Gnomad OTH AF: 0.0536

GnomAD4 exome AF: 0.0695 AC: 92582 AN: 1332082 Hom.: 3619 Cov.: 20 AF XY: 0.0700 AC XY: 46498 AN XY: 664130

African (AFR) AF: 0.0155 AC: 481 AN: 31030

American (AMR) AF: 0.0409 AC: 1585 AN: 38728

Ashkenazi Jewish (ASJ) AF: 0.0347 AC: 862 AN: 24856

East Asian (EAS) AF: 0.0714 AC: 2646 AN: 37054

South Asian (SAS) AF: 0.0812 AC: 6580 AN: 81060

European-Finnish (FIN) AF: 0.0746 AC: 3244 AN: 43498

Middle Eastern (MID) AF: 0.0680 AC: 280 AN: 4120

European-Non Finnish (NFE) AF: 0.0718 AC: 72990 AN: 1016000

Other (OTH) AF: 0.0702 AC: 3914 AN: 55736

GnomAD4 genome AF: 0.0559 AC: 8516 AN: 152232 Hom.: 267 Cov.: 33 AF XY: 0.0565 AC XY: 4202 AN XY: 74434

African (AFR) AF: 0.0185 AC: 770 AN: 41544

American (AMR) AF: 0.0409 AC: 626 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0415 AC: 144 AN: 3470

East Asian (EAS) AF: 0.102 AC: 526 AN: 5168

South Asian (SAS) AF: 0.0876 AC: 423 AN: 4828

European-Finnish (FIN) AF: 0.0743 AC: 788 AN: 10600

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0740 AC: 5033 AN: 68002

Other (OTH) AF: 0.0535 AC: 113 AN: 2112

Alfa AF: 0.0707 Hom.: 507

Bravo AF: 0.0516

Asia WGS AF: 0.0830 AC: 289 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.5
DANN	Benign	0.57
PhyloP100		0.32
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: rs3025017; hg19: chr6-43748357;