rs833068

Variant names:

• chr6-43774790-G-A
• rs833068
• ENST00000480614.1:n.1619G>A

Variant summary

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

The ENST00000480614.1(VEGFA):​n.1619G>A 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 0.343 in 326,118 control chromosomes in the GnomAD database, including 20,111 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 0.36 (10374 hom., cov: 32)
  • Exomes 𝑓: 0.33 (9737 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.972
• Publications: 83 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=-0.79).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.658+398G>A		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+398G>A		intron_variant	Intron 2 of 7		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.363 AC: 55065 AN: 151862 Hom.: 10364 Cov.: 32

Gnomad AFR AF: 0.470

Gnomad AMI AF: 0.197

Gnomad AMR AF: 0.372

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.276

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.316

Gnomad OTH AF: 0.390

GnomAD4 exome AF: 0.327 AC: 56894 AN: 174138 Hom.: 9737 Cov.: 0 AF XY: 0.322 AC XY: 29805 AN XY: 92494

African (AFR) AF: 0.480 AC: 2917 AN: 6074

American (AMR) AF: 0.367 AC: 3204 AN: 8720

Ashkenazi Jewish (ASJ) AF: 0.427 AC: 2138 AN: 5006

East Asian (EAS) AF: 0.421 AC: 4348 AN: 10336

South Asian (SAS) AF: 0.280 AC: 6830 AN: 24428

European-Finnish (FIN) AF: 0.235 AC: 1780 AN: 7570

Middle Eastern (MID) AF: 0.419 AC: 300 AN: 716

European-Non Finnish (NFE) AF: 0.317 AC: 32291 AN: 101800

Other (OTH) AF: 0.325 AC: 3086 AN: 9488

GnomAD4 genome AF: 0.363 AC: 55102 AN: 151980 Hom.: 10374 Cov.: 32 AF XY: 0.358 AC XY: 26608 AN XY: 74286

African (AFR) AF: 0.469 AC: 19438 AN: 41424

American (AMR) AF: 0.372 AC: 5682 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1440 AN: 3470

East Asian (EAS) AF: 0.414 AC: 2139 AN: 5166

South Asian (SAS) AF: 0.275 AC: 1326 AN: 4814

European-Finnish (FIN) AF: 0.232 AC: 2458 AN: 10582

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.316 AC: 21490 AN: 67936

Other (OTH) AF: 0.392 AC: 828 AN: 2112

Alfa AF: 0.338 Hom.: 15639

Bravo AF: 0.385

Asia WGS AF: 0.318 AC: 1103 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		0.97
PromoterAI		0.021	Neutral
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: rs833068; hg19: chr6-43742527;