rs3025015

Positions:

• chr6-43780613-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003376.6(VEGFA):​c.963-119G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0506 in 1,459,574 control chromosomes in the GnomAD database, including 2,180 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 0.044 (194 hom., cov: 33)
  • Exomes 𝑓: 0.051 (1986 hom.)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.882

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]

POLR1C (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.074 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VEGFA	NM_003376.6	c.963-119G>A		intron_variant		ENST00000672860.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VEGFA	ENST00000672860.3	c.963-119G>A		intron_variant			NM_003376.6

Frequencies

GnomAD3 genomes AF: 0.0438 AC: 6656 AN: 152102 Hom.: 193 Cov.: 33

Gnomad AFR AF: 0.0165

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0367

Gnomad ASJ AF: 0.0161

Gnomad EAS AF: 0.0802

Gnomad SAS AF: 0.0629

Gnomad FIN AF: 0.0719

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0555

Gnomad OTH AF: 0.0377

GnomAD4 exome AF: 0.0513 AC: 67118 AN: 1307354 Hom.: 1986 Cov.: 19 AF XY: 0.0516 AC XY: 33620 AN XY: 651816

Gnomad4 AFR exome AF: 0.0131

Gnomad4 AMR exome AF: 0.0236

Gnomad4 ASJ exome AF: 0.0155

Gnomad4 EAS exome AF: 0.0417

Gnomad4 SAS exome AF: 0.0579

Gnomad4 FIN exome AF: 0.0662

Gnomad4 NFE exome AF: 0.0541

Gnomad4 OTH exome AF: 0.0457

GnomAD4 genome AF: 0.0438 AC: 6664 AN: 152220 Hom.: 194 Cov.: 33 AF XY: 0.0444 AC XY: 3305 AN XY: 74412

Gnomad4 AFR AF: 0.0165

Gnomad4 AMR AF: 0.0368

Gnomad4 ASJ AF: 0.0161

Gnomad4 EAS AF: 0.0804

Gnomad4 SAS AF: 0.0627

Gnomad4 FIN AF: 0.0719

Gnomad4 NFE AF: 0.0555

Gnomad4 OTH AF: 0.0406

Alfa AF: 0.0502 Hom.: 156

Bravo AF: 0.0384

Asia WGS AF: 0.0690 AC: 238 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.6
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs3025015; hg19: chr6-43748350;