chr6-43781373-C-T

Variant names:

• chr6-43781373-C-T
• rs3025020
• ENST00000480614.1:n.7056C>T

Variant summary

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

The ENST00000480614.1(VEGFA):​n.7056C>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 0.259 in 247,446 control chromosomes in the GnomAD database, including 9,557 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 0.24 (5105 hom., cov: 34)
  • Exomes 𝑓: 0.29 (4452 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 54 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 (SAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.1034+570C>T		intron_variant	Intron 6 of 7	ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.1034+570C>T		intron_variant	Intron 6 of 7		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.239 AC: 36417 AN: 152112 Hom.: 5107 Cov.: 34

Gnomad AFR AF: 0.0894

Gnomad AMI AF: 0.424

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.339

Gnomad SAS AF: 0.360

Gnomad FIN AF: 0.280

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.239

GnomAD4 exome AF: 0.290 AC: 27652 AN: 95216 Hom.: 4452 Cov.: 0 AF XY: 0.299 AC XY: 15039 AN XY: 50300

African (AFR) AF: 0.0782 AC: 230 AN: 2940

American (AMR) AF: 0.279 AC: 1122 AN: 4020

Ashkenazi Jewish (ASJ) AF: 0.288 AC: 639 AN: 2220

East Asian (EAS) AF: 0.340 AC: 1456 AN: 4280

South Asian (SAS) AF: 0.366 AC: 5460 AN: 14902

European-Finnish (FIN) AF: 0.273 AC: 1116 AN: 4090

Middle Eastern (MID) AF: 0.339 AC: 126 AN: 372

European-Non Finnish (NFE) AF: 0.281 AC: 16151 AN: 57534

Other (OTH) AF: 0.278 AC: 1352 AN: 4858

GnomAD4 genome AF: 0.239 AC: 36431 AN: 152230 Hom.: 5105 Cov.: 34 AF XY: 0.242 AC XY: 17997 AN XY: 74428

African (AFR) AF: 0.0891 AC: 3705 AN: 41574

American (AMR) AF: 0.259 AC: 3956 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1089 AN: 3470

East Asian (EAS) AF: 0.338 AC: 1742 AN: 5150

South Asian (SAS) AF: 0.363 AC: 1752 AN: 4830

European-Finnish (FIN) AF: 0.280 AC: 2969 AN: 10610

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.298 AC: 20261 AN: 67974

Other (OTH) AF: 0.238 AC: 504 AN: 2114

Alfa AF: 0.270 Hom.: 1340

Bravo AF: 0.231

Asia WGS AF: 0.277 AC: 962 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.3
DANN	Benign	0.77
PhyloP100		-1.0
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: rs3025020; hg19: chr6-43749110;