rs3025039

Variant names:

• chr6-43784799-C-T
• rs3025039
• ENST00000480614.1:n.10482C>T

Variant summary

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

The ENST00000480614.1(VEGFA):​n.10482C>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 0.143 in 701,944 control chromosomes in the GnomAD database, including 7,913 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency:
  • Genomes: 𝑓 0.13 (1464 hom., cov: 31)
  • Exomes 𝑓: 0.15 (6449 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 0.0550
• Publications: 842 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=-0.48).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.171 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.*237C>T		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.*237C>T		3_prime_UTR_variant	Exon 8 of 8		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19602 AN: 151728 Hom.: 1462 Cov.: 31

Gnomad AFR AF: 0.0849

Gnomad AMI AF: 0.0802

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.132

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.0972

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.127

GnomAD4 exome AF: 0.146 AC: 80486 AN: 550102 Hom.: 6449 Cov.: 6 AF XY: 0.143 AC XY: 41724 AN XY: 292778

African (AFR) AF: 0.0853 AC: 1268 AN: 14862

American (AMR) AF: 0.270 AC: 8518 AN: 31552

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 2555 AN: 18900

East Asian (EAS) AF: 0.196 AC: 6216 AN: 31736

South Asian (SAS) AF: 0.0975 AC: 5748 AN: 58976

European-Finnish (FIN) AF: 0.149 AC: 6134 AN: 41048

Middle Eastern (MID) AF: 0.130 AC: 435 AN: 3356

European-Non Finnish (NFE) AF: 0.142 AC: 45507 AN: 320018

Other (OTH) AF: 0.138 AC: 4105 AN: 29654

GnomAD4 genome AF: 0.129 AC: 19624 AN: 151842 Hom.: 1464 Cov.: 31 AF XY: 0.130 AC XY: 9650 AN XY: 74200

African (AFR) AF: 0.0850 AC: 3521 AN: 41440

American (AMR) AF: 0.176 AC: 2690 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 458 AN: 3464

East Asian (EAS) AF: 0.175 AC: 902 AN: 5148

South Asian (SAS) AF: 0.0982 AC: 470 AN: 4788

European-Finnish (FIN) AF: 0.151 AC: 1583 AN: 10504

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9617 AN: 67940

Other (OTH) AF: 0.127 AC: 268 AN: 2106

Alfa AF: 0.140 Hom.: 4954

Bravo AF: 0.134

Asia WGS AF: 0.138 AC: 481 AN: 3478

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Cholangiocarcinoma Other:1

Dec 10, 2022

Department of Surgery, Campus Charité Mitte Campus Virchow-klinikum, Charite-Universitaetsmedizin Berlin

Significance: other

Review Status: no assertion criteria provided

Collection Method: research

No association with disease-free or overall survival after resection of intrahepatic Cholangiocarcinoma No association with disease-free or overall survival

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		0.055
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=93/7	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: rs3025039; hg19: chr6-43752536; COSMIC: COSV57878013; COSMIC: COSV57878013;