6-43785475-A-G

Position:

• chr6-43785475-A-G

Variant summary

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

The NM_003376.6(VEGFA):​c.*913A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 219,758 control chromosomes in the GnomAD database, including 40,015 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 0.59 (27182 hom., cov: 33)
  • Exomes 𝑓: 0.60 (12833 hom.)
• Consequence: VEGFA NM_003376.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.365

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.764 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.*913A>G		3_prime_UTR_variant	8/8	ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.*913A>G		3_prime_UTR_variant	8/8		NM_003376.6	ENSP00000500082.3

Frequencies

GnomAD3 genomes AF: 0.593 AC: 90130 AN: 151976 Hom.: 27144 Cov.: 33

Gnomad AFR AF: 0.642

Gnomad AMI AF: 0.529

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.783

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.527

Gnomad MID AF: 0.570

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.597

GnomAD4 exome AF: 0.603 AC: 40781 AN: 67664 Hom.: 12833 Cov.: 0 AF XY: 0.601 AC XY: 18787 AN XY: 31276

Gnomad4 AFR exome AF: 0.645

Gnomad4 AMR exome AF: 0.721

Gnomad4 ASJ exome AF: 0.550

Gnomad4 EAS exome AF: 0.865

Gnomad4 SAS exome AF: 0.613

Gnomad4 FIN exome AF: 0.552

Gnomad4 NFE exome AF: 0.539

Gnomad4 OTH exome AF: 0.580

GnomAD4 genome AF: 0.593 AC: 90216 AN: 152094 Hom.: 27182 Cov.: 33 AF XY: 0.597 AC XY: 44377 AN XY: 74368

Gnomad4 AFR AF: 0.642

Gnomad4 AMR AF: 0.693

Gnomad4 ASJ AF: 0.561

Gnomad4 EAS AF: 0.784

Gnomad4 SAS AF: 0.601

Gnomad4 FIN AF: 0.527

Gnomad4 NFE AF: 0.539

Gnomad4 OTH AF: 0.596

Alfa AF: 0.552 Hom.: 20360

Bravo AF: 0.610

Asia WGS AF: 0.663 AC: 2304 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.6
DANN	Benign	0.69
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: rs10434; hg19: chr6-43753212;