6-43783338-A-G

Variant names:

• chr6-43783338-A-G
• rs3025033
• ENST00000480614.1:n.9021A>G

Variant summary

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

The ENST00000480614.1(VEGFA):​n.9021A>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 0.179 in 152,102 control chromosomes in the GnomAD database, including 2,630 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 0.18 (2629 hom., cov: 31)
  • Exomes 𝑓: 0.17 (1 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.43
• Publications: 50 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.218 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000480614.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	NM_003376.6	MANE Select	c.1167-1203A>G		intron	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.1218-1203A>G		intron	N/A	NP_001020537.2
	VEGFA	NM_001025367.3		c.1149-1203A>G		intron	N/A	NP_001020538.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	ENST00000480614.1	TSL:1	n.9021A>G		non_coding_transcript_exon	Exon 3 of 3
	VEGFA	ENST00000672860.3	MANE Select	c.1167-1203A>G		intron	N/A	ENSP00000500082.3
	VEGFA	ENST00000372055.9	TSL:1	c.1218-1203A>G		intron	N/A	ENSP00000361125.5

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27179 AN: 151774 Hom.: 2620 Cov.: 31

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.220

Gnomad ASJ AF: 0.167

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.103

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.155

Gnomad OTH AF: 0.181

GnomAD4 exome AF: 0.167 AC: 35 AN: 210 Hom.: 1 Cov.: 0 AF XY: 0.169 AC XY: 21 AN XY: 124

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.0833 AC: 1 AN: 12

South Asian (SAS) AF: 0.00 AC: 0 AN: 2

European-Finnish (FIN) AF: 0.250 AC: 10 AN: 40

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.131 AC: 17 AN: 130

Other (OTH) AF: 0.200 AC: 4 AN: 20

GnomAD4 genome AF: 0.179 AC: 27230 AN: 151892 Hom.: 2629 Cov.: 31 AF XY: 0.179 AC XY: 13258 AN XY: 74236

African (AFR) AF: 0.221 AC: 9162 AN: 41392

American (AMR) AF: 0.221 AC: 3372 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 578 AN: 3470

East Asian (EAS) AF: 0.178 AC: 916 AN: 5156

South Asian (SAS) AF: 0.104 AC: 499 AN: 4818

European-Finnish (FIN) AF: 0.156 AC: 1648 AN: 10544

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.155 AC: 10541 AN: 67930

Other (OTH) AF: 0.181 AC: 380 AN: 2104

Alfa AF: 0.171 Hom.: 2034

Bravo AF: 0.191

Asia WGS AF: 0.159 AC: 552 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.6
DANN	Benign	0.81
PhyloP100		-1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs3025033; hg19: chr6-43751075;