6-43781426-T-C

Variant names:

• chr6-43781426-T-C
• rs3025021
• ENST00000480614.1:n.7109T>C

Variant summary

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

The ENST00000480614.1(VEGFA):​n.7109T>C 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 0.689 in 236,326 control chromosomes in the GnomAD database, including 56,800 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 0.70 (37417 hom., cov: 36)
  • Exomes 𝑓: 0.67 (19383 hom.)
• Consequence: VEGFA ENST00000480614.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.604
• Publications: 30 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=-0.68).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.835 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000480614.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	NM_003376.6	MANE Select	c.1035-530T>C		intron	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.1086-530T>C		intron	N/A	NP_001020537.2
	VEGFA	NM_001025367.3		c.1017-530T>C		intron	N/A	NP_001020538.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	ENST00000480614.1	TSL:1	n.7109T>C		non_coding_transcript_exon	Exon 3 of 3
	VEGFA	ENST00000672860.3	MANE Select	c.1035-530T>C		intron	N/A	ENSP00000500082.3
	VEGFA	ENST00000372055.9	TSL:1	c.1086-530T>C		intron	N/A	ENSP00000361125.5

Frequencies

GnomAD3 genomes AF: 0.699 AC: 106264 AN: 152102 Hom.: 37367 Cov.: 36

Gnomad AFR AF: 0.763

Gnomad AMI AF: 0.666

Gnomad AMR AF: 0.663

Gnomad ASJ AF: 0.625

Gnomad EAS AF: 0.856

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.654

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.673

GnomAD4 exome AF: 0.671 AC: 56394 AN: 84106 Hom.: 19383 Cov.: 0 AF XY: 0.676 AC XY: 29757 AN XY: 44042

African (AFR) AF: 0.757 AC: 1893 AN: 2500

American (AMR) AF: 0.689 AC: 2677 AN: 3888

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 1132 AN: 1946

East Asian (EAS) AF: 0.855 AC: 3467 AN: 4056

South Asian (SAS) AF: 0.714 AC: 9053 AN: 12682

European-Finnish (FIN) AF: 0.634 AC: 2251 AN: 3552

Middle Eastern (MID) AF: 0.628 AC: 211 AN: 336

European-Non Finnish (NFE) AF: 0.647 AC: 32897 AN: 50838

Other (OTH) AF: 0.653 AC: 2813 AN: 4308

GnomAD4 genome AF: 0.699 AC: 106376 AN: 152220 Hom.: 37417 Cov.: 36 AF XY: 0.700 AC XY: 52094 AN XY: 74418

African (AFR) AF: 0.763 AC: 31713 AN: 41540

American (AMR) AF: 0.664 AC: 10160 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 2169 AN: 3470

East Asian (EAS) AF: 0.856 AC: 4419 AN: 5164

South Asian (SAS) AF: 0.740 AC: 3576 AN: 4830

European-Finnish (FIN) AF: 0.654 AC: 6939 AN: 10604

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.665 AC: 45191 AN: 67994

Other (OTH) AF: 0.675 AC: 1429 AN: 2116

Alfa AF: 0.702 Hom.: 16710

Bravo AF: 0.701

Asia WGS AF: 0.773 AC: 2689 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	10
DANN	Benign	0.82
PhyloP100		0.60
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: rs3025021; hg19: chr6-43749163;