chr6-43785588-G-A

Position:

• chr6-43785588-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.*1026G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0889 in 206,052 control chromosomes in the GnomAD database, including 1,025 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 0.087 (755 hom., cov: 32)
  • Exomes 𝑓: 0.094 (270 hom.)
• Consequence: VEGFA NM_003376.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.70

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=-0.85).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VEGFA	NM_003376.6	c.*1026G>A		3_prime_UTR_variant	8/8	ENST00000672860.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VEGFA	ENST00000672860.3	c.*1026G>A		3_prime_UTR_variant	8/8		NM_003376.6

Frequencies

GnomAD3 genomes AF: 0.0874 AC: 13289 AN: 152044 Hom.: 755 Cov.: 32

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.125

Gnomad AMR AF: 0.0652

Gnomad ASJ AF: 0.0737

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.143

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.118

Gnomad OTH AF: 0.0746

GnomAD4 exome AF: 0.0935 AC: 5041 AN: 53890 Hom.: 270 Cov.: 0 AF XY: 0.0919 AC XY: 2318 AN XY: 25224

Gnomad4 AFR exome AF: 0.0176

Gnomad4 AMR exome AF: 0.0486

Gnomad4 ASJ exome AF: 0.0718

Gnomad4 EAS exome AF: 0.0489

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.114

Gnomad4 OTH exome AF: 0.0990

GnomAD4 genome AF: 0.0873 AC: 13279 AN: 152162 Hom.: 755 Cov.: 32 AF XY: 0.0888 AC XY: 6610 AN XY: 74402

Gnomad4 AFR AF: 0.0210

Gnomad4 AMR AF: 0.0651

Gnomad4 ASJ AF: 0.0737

Gnomad4 EAS AF: 0.130

Gnomad4 SAS AF: 0.142

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.118

Gnomad4 OTH AF: 0.0757

Alfa AF: 0.103 Hom.: 853

Bravo AF: 0.0755

Asia WGS AF: 0.129 AC: 449 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	12
DANN	Benign	0.62

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs3025053; hg19: chr6-43753325;