rs3025046

Variant names:

• chr6-43777715-C-G
• rs3025046
• ENST00000512683.1:n.365C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000512683.1(VEGFA):​n.365C>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 0.000155 in 1,480,424 control chromosomes in the GnomAD database, including 1 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 0.00073 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: VEGFA ENST00000512683.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.273
• Publications: 1 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BS2: High AC in GnomAd4 at 111 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.855+50C>G		intron_variant	Intron 3 of 7	ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.855+50C>G		intron_variant	Intron 3 of 7		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.000730 AC: 111 AN: 152010 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000991

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00341

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000369 AC: 79 AN: 214348 AF XY: 0.000303

Gnomad AFR exome AF: 0.000952

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000925

GnomAD4 exome AF: 0.0000896 AC: 119 AN: 1328296 Hom.: 0 Cov.: 24 AF XY: 0.0000758 AC XY: 50 AN XY: 659806

African (AFR) AF: 0.000331 AC: 10 AN: 30208

American (AMR) AF: 0.000965 AC: 39 AN: 40398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21888

East Asian (EAS) AF: 0.00 AC: 0 AN: 32998

South Asian (SAS) AF: 0.0000245 AC: 2 AN: 81698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43720

Middle Eastern (MID) AF: 0.000766 AC: 4 AN: 5222

European-Non Finnish (NFE) AF: 0.0000540 AC: 55 AN: 1018494

Other (OTH) AF: 0.000168 AC: 9 AN: 53670

GnomAD4 genome AF: 0.000730 AC: 111 AN: 152128 Hom.: 1 Cov.: 32 AF XY: 0.000834 AC XY: 62 AN XY: 74368

African (AFR) AF: 0.000988 AC: 41 AN: 41490

American (AMR) AF: 0.00340 AC: 52 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000191 AC: 13 AN: 67978

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.000256 Hom.: 0

Bravo AF: 0.000771

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.3
DANN	Benign	0.42
PhyloP100		-0.27
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.4

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: rs3025046; hg19: chr6-43745452;