ENST00000480614.1:n.2599C>T

Variant names:

• chr6-43775770-C-T
• rs3024994
• ENST00000480614.1:n.2599C>T

Variant summary

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

The ENST00000480614.1(VEGFA):​n.2599C>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 0.0382 in 152,294 control chromosomes in the GnomAD database, including 161 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 0.038 (160 hom., cov: 32)
  • Exomes 𝑓: 0.20 (1 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0260
• Publications: 34 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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.658+1378C>T		intron_variant	Intron 2 of 7	ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.658+1378C>T		intron_variant	Intron 2 of 7		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.0382 AC: 5818 AN: 152166 Hom.: 160 Cov.: 32

Gnomad AFR AF: 0.00881

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0364

Gnomad ASJ AF: 0.0150

Gnomad EAS AF: 0.0654

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0644

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0541

Gnomad OTH AF: 0.0368

GnomAD4 exome AF: 0.200 AC: 2 AN: 10 Hom.: 1 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 1.00 AC: 2 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 8

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0382 AC: 5816 AN: 152284 Hom.: 160 Cov.: 32 AF XY: 0.0385 AC XY: 2864 AN XY: 74450

African (AFR) AF: 0.00878 AC: 365 AN: 41572

American (AMR) AF: 0.0364 AC: 557 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0150 AC: 52 AN: 3472

East Asian (EAS) AF: 0.0653 AC: 339 AN: 5190

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4826

European-Finnish (FIN) AF: 0.0644 AC: 683 AN: 10598

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0541 AC: 3680 AN: 68010

Other (OTH) AF: 0.0369 AC: 78 AN: 2114

Alfa AF: 0.0471 Hom.: 461

Bravo AF: 0.0341

Asia WGS AF: 0.0500 AC: 174 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.2
DANN	Benign	0.77
PhyloP100		0.026
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: rs3024994; hg19: chr6-43743507;