6-43781058-C-G

Position:

• chr6-43781058-C-G

Variant summary

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

The NM_003376.6(VEGFA):​c.1034+255C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0696 in 848,848 control chromosomes in the GnomAD database, including 2,512 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 0.063 (439 hom., cov: 33)
  • Exomes 𝑓: 0.071 (2073 hom.)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48

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=-0.48).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VEGFA	NM_003376.6	c.1034+255C>G		intron_variant		ENST00000672860.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VEGFA	ENST00000672860.3	c.1034+255C>G		intron_variant			NM_003376.6

Frequencies

GnomAD3 genomes AF: 0.0628 AC: 9552 AN: 152012 Hom.: 439 Cov.: 33

Gnomad AFR AF: 0.0163

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.0501

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.0797

Gnomad FIN AF: 0.133

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0792

Gnomad OTH AF: 0.0594

GnomAD4 exome AF: 0.0711 AC: 49548 AN: 696718 Hom.: 2073 Cov.: 9 AF XY: 0.0709 AC XY: 25199 AN XY: 355614

Gnomad4 AFR exome AF: 0.0152

Gnomad4 AMR exome AF: 0.0372

Gnomad4 ASJ exome AF: 0.0253

Gnomad4 EAS exome AF: 0.0760

Gnomad4 SAS exome AF: 0.0709

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.0736

Gnomad4 OTH exome AF: 0.0680

GnomAD4 genome AF: 0.0628 AC: 9552 AN: 152130 Hom.: 439 Cov.: 33 AF XY: 0.0653 AC XY: 4856 AN XY: 74376

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.0501

Gnomad4 ASJ AF: 0.0259

Gnomad4 EAS AF: 0.131

Gnomad4 SAS AF: 0.0789

Gnomad4 FIN AF: 0.133

Gnomad4 NFE AF: 0.0792

Gnomad4 OTH AF: 0.0602

Alfa AF: 0.0425 Hom.: 58

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.66
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.2

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: rs3025018; hg19: chr6-43748795;