rs3025053

Variant names:

• chr6-43785588-G-A
• rs3025053
• ENST00000480614.1:n.11271G>A

Variant summary

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

The ENST00000480614.1(VEGFA):​n.11271G>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 0.0889 in 206,052 control chromosomes in the GnomAD database, including 1,025 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 0.087 (755 hom., cov: 32)
  • Exomes 𝑓: 0.094 (270 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.70
• Publications: 31 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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.*1026G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.*1026G>A		3_prime_UTR_variant	Exon 8 of 8		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.0874 AC: 13289 AN: 152044 Hom.: 755 Cov.: 32

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0652

Gnomad ASJ AF: 0.0737

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.0746

GnomAD4 exome AF: 0.0935 AC: 5041 AN: 53890 Hom.: 270 Cov.: 0 AF XY: 0.0919 AC XY: 2318 AN XY: 25224

African (AFR) AF: 0.0176 AC: 39 AN: 2216

American (AMR) AF: 0.0486 AC: 73 AN: 1502

Ashkenazi Jewish (ASJ) AF: 0.0718 AC: 246 AN: 3428

East Asian (EAS) AF: 0.0489 AC: 407 AN: 8330

South Asian (SAS) AF: 0.107 AC: 53 AN: 494

European-Finnish (FIN) AF: 0.108 AC: 51 AN: 474

Middle Eastern (MID) AF: 0.0472 AC: 15 AN: 318

European-Non Finnish (NFE) AF: 0.114 AC: 3717 AN: 32684

Other (OTH) AF: 0.0990 AC: 440 AN: 4444

GnomAD4 genome AF: 0.0873 AC: 13279 AN: 152162 Hom.: 755 Cov.: 32 AF XY: 0.0888 AC XY: 6610 AN XY: 74402

African (AFR) AF: 0.0210 AC: 872 AN: 41546

American (AMR) AF: 0.0651 AC: 995 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0737 AC: 256 AN: 3472

East Asian (EAS) AF: 0.130 AC: 672 AN: 5170

South Asian (SAS) AF: 0.142 AC: 686 AN: 4822

European-Finnish (FIN) AF: 0.141 AC: 1490 AN: 10590

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.118 AC: 8025 AN: 67962

Other (OTH) AF: 0.0757 AC: 159 AN: 2100

Alfa AF: 0.0990 Hom.: 1217

Bravo AF: 0.0755

Asia WGS AF: 0.129 AC: 449 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	12
DANN	Benign	0.62
PhyloP100		2.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3025053; hg19: chr6-43753325;