6-43781058-C-T

Variant names:

• chr6-43781058-C-T
• rs3025018
• ENST00000480614.1:n.6741C>T

Variant summary

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

The ENST00000480614.1(VEGFA):​n.6741C>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 0.117 in 848,584 control chromosomes in the GnomAD database, including 6,284 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 0.12 (1177 hom., cov: 33)
  • Exomes 𝑓: 0.12 (5107 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48
• Publications: 6 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=-0.55).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.169 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.1034+255C>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+255C>T		intron_variant	Intron 6 of 7		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18317 AN: 151990 Hom.: 1177 Cov.: 33

Gnomad AFR AF: 0.115

Gnomad AMI AF: 0.109

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.179

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.134

Gnomad NFE AF: 0.115

Gnomad OTH AF: 0.114

GnomAD4 exome AF: 0.116 AC: 80825 AN: 696476 Hom.: 5107 Cov.: 9 AF XY: 0.115 AC XY: 40944 AN XY: 355510

African (AFR) AF: 0.107 AC: 1862 AN: 17448

American (AMR) AF: 0.188 AC: 4543 AN: 24176

Ashkenazi Jewish (ASJ) AF: 0.112 AC: 1794 AN: 16022

East Asian (EAS) AF: 0.219 AC: 6912 AN: 31620

South Asian (SAS) AF: 0.0993 AC: 5303 AN: 53420

European-Finnish (FIN) AF: 0.123 AC: 3634 AN: 29624

Middle Eastern (MID) AF: 0.135 AC: 335 AN: 2488

European-Non Finnish (NFE) AF: 0.107 AC: 52412 AN: 487574

Other (OTH) AF: 0.118 AC: 4030 AN: 34104

GnomAD4 genome AF: 0.120 AC: 18328 AN: 152108 Hom.: 1177 Cov.: 33 AF XY: 0.122 AC XY: 9050 AN XY: 74362

African (AFR) AF: 0.114 AC: 4740 AN: 41480

American (AMR) AF: 0.154 AC: 2348 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3472

East Asian (EAS) AF: 0.179 AC: 922 AN: 5162

South Asian (SAS) AF: 0.103 AC: 498 AN: 4824

European-Finnish (FIN) AF: 0.115 AC: 1223 AN: 10594

Middle Eastern (MID) AF: 0.134 AC: 39 AN: 292

European-Non Finnish (NFE) AF: 0.115 AC: 7828 AN: 67968

Other (OTH) AF: 0.117 AC: 246 AN: 2110

Alfa AF: 0.102 Hom.: 268

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		1.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.2
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: rs3025018; hg19: chr6-43748795;