rs2146323

Positions:

• chr6-43777358-C-A

Variant summary

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

The NM_003376.6(VEGFA):​c.659-111C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,249,802 control chromosomes in the GnomAD database, including 72,912 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 0.31 (7443 hom., cov: 33)
  • Exomes 𝑓: 0.34 (65469 hom.)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.493

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=-0.65).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.393 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.659-111C>A		intron_variant		ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.659-111C>A		intron_variant			NM_003376.6	ENSP00000500082

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47270 AN: 152024 Hom.: 7441 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.298

GnomAD4 exome AF: 0.342 AC: 375654 AN: 1097660 Hom.: 65469 Cov.: 15 AF XY: 0.345 AC XY: 192426 AN XY: 557896

Gnomad4 AFR exome AF: 0.214

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.296

Gnomad4 EAS exome AF: 0.277

Gnomad4 SAS exome AF: 0.410

Gnomad4 FIN exome AF: 0.383

Gnomad4 NFE exome AF: 0.343

Gnomad4 OTH exome AF: 0.337

GnomAD4 genome AF: 0.311 AC: 47300 AN: 152142 Hom.: 7443 Cov.: 33 AF XY: 0.315 AC XY: 23458 AN XY: 74374

Gnomad4 AFR AF: 0.219

Gnomad4 AMR AF: 0.316

Gnomad4 ASJ AF: 0.305

Gnomad4 EAS AF: 0.262

Gnomad4 SAS AF: 0.408

Gnomad4 FIN AF: 0.388

Gnomad4 NFE AF: 0.350

Gnomad4 OTH AF: 0.298

Alfa AF: 0.334 Hom.: 11864

Bravo AF: 0.296

Asia WGS AF: 0.370 AC: 1283 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Benign	0.85

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: rs2146323; hg19: chr6-43745095;