6-43783622-C-T

Variant names:

• chr6-43783622-C-T
• rs3025035
• ENST00000480614.1:n.9305C>T

Variant summary

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

The ENST00000480614.1(VEGFA):​n.9305C>T 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 0.136 in 152,552 control chromosomes in the GnomAD database, including 1,960 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 0.14 (1956 hom., cov: 31)
  • Exomes 𝑓: 0.092 (4 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.06
• Publications: 60 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.268 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.1167-919C>T		intron	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.1218-919C>T		intron	N/A	NP_001020537.2
	VEGFA	NM_001025367.3		c.1149-919C>T		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.9305C>T		non_coding_transcript_exon	Exon 3 of 3
	VEGFA	ENST00000672860.3	MANE Select	c.1167-919C>T		intron	N/A	ENSP00000500082.3
	VEGFA	ENST00000372055.9	TSL:1	c.1218-919C>T		intron	N/A	ENSP00000361125.5

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20620 AN: 151922 Hom.: 1954 Cov.: 31

Gnomad AFR AF: 0.273

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0516

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0794

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0738

Gnomad OTH AF: 0.142

GnomAD4 exome AF: 0.0918 AC: 47 AN: 512 Hom.: 4 Cov.: 0 AF XY: 0.0933 AC XY: 25 AN XY: 268

African (AFR) AF: 0.214 AC: 6 AN: 28

American (AMR) AF: 0.0714 AC: 1 AN: 14

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16

East Asian (EAS) AF: 0.259 AC: 15 AN: 58

South Asian (SAS) AF: 0.00 AC: 0 AN: 4

European-Finnish (FIN) AF: 0.0811 AC: 6 AN: 74

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.0603 AC: 17 AN: 282

Other (OTH) AF: 0.0625 AC: 2 AN: 32

GnomAD4 genome AF: 0.136 AC: 20634 AN: 152040 Hom.: 1956 Cov.: 31 AF XY: 0.135 AC XY: 10054 AN XY: 74326

African (AFR) AF: 0.273 AC: 11287 AN: 41400

American (AMR) AF: 0.103 AC: 1570 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0516 AC: 179 AN: 3470

East Asian (EAS) AF: 0.172 AC: 892 AN: 5172

South Asian (SAS) AF: 0.106 AC: 509 AN: 4812

European-Finnish (FIN) AF: 0.0794 AC: 840 AN: 10580

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0737 AC: 5013 AN: 67990

Other (OTH) AF: 0.141 AC: 298 AN: 2106

Alfa AF: 0.0878 Hom.: 2188

Bravo AF: 0.142

Asia WGS AF: 0.152 AC: 527 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.0
DANN	Benign	0.58
PhyloP100		1.1
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: rs3025035; hg19: chr6-43751359;