6-43785314-C-T

Position:

• chr6-43785314-C-T

Variant summary

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

The NM_003376.6(VEGFA):​c.*752C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 209,370 control chromosomes in the GnomAD database, including 2,376 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 0.15 (1734 hom., cov: 31)
  • Exomes 𝑓: 0.15 (642 hom.)
• Consequence: VEGFA NM_003376.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.311

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=-0.9).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VEGFA	NM_003376.6	c.*752C>T		3_prime_UTR_variant	8/8	ENST00000672860.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VEGFA	ENST00000672860.3	c.*752C>T		3_prime_UTR_variant	8/8		NM_003376.6

Frequencies

GnomAD3 genomes AF: 0.145 AC: 22108 AN: 152010 Hom.: 1732 Cov.: 31

Gnomad AFR AF: 0.137

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.184

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.177

Gnomad SAS AF: 0.0974

Gnomad FIN AF: 0.155

Gnomad MID AF: 0.153

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.145

GnomAD4 exome AF: 0.148 AC: 8448 AN: 57242 Hom.: 642 Cov.: 0 AF XY: 0.148 AC XY: 3952 AN XY: 26672

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.211

Gnomad4 ASJ exome AF: 0.125

Gnomad4 EAS exome AF: 0.193

Gnomad4 SAS exome AF: 0.0956

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.138

Gnomad4 OTH exome AF: 0.141

GnomAD4 genome AF: 0.145 AC: 22127 AN: 152128 Hom.: 1734 Cov.: 31 AF XY: 0.146 AC XY: 10825 AN XY: 74372

Gnomad4 AFR AF: 0.137

Gnomad4 AMR AF: 0.184

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.178

Gnomad4 SAS AF: 0.0983

Gnomad4 FIN AF: 0.155

Gnomad4 NFE AF: 0.143

Gnomad4 OTH AF: 0.145

Alfa AF: 0.113 Hom.: 312

Bravo AF: 0.152

Asia WGS AF: 0.141 AC: 490 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.1
DANN	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3025040; hg19: chr6-43753051; COSMIC: COSV57877549; COSMIC: COSV57877549;