rs28357093

Variant names:

• chr6-43770068-A-C
• rs28357093
• NM_003376.6:c.-639A>C

Variant summary

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

The NM_003376.6(VEGFA):​c.-639A>C variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0451 in 293,628 control chromosomes in the GnomAD database, including 418 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 0.045 (235 hom., cov: 33)
  • Exomes 𝑓: 0.045 (183 hom.)
• Consequence: VEGFA NM_003376.6 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0970

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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.-639A>C		upstream_gene_variant		ENST00000672860.3	NP_003367.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VEGFA	ENST00000672860.3	c.-639A>C		upstream_gene_variant			NM_003376.6	ENSP00000500082.3
VEGFA	ENST00000425836.9	c.-639A>C		upstream_gene_variant		1		ENSP00000388465.4
VEGFA	ENST00000372067.8	c.-639A>C		upstream_gene_variant		1		ENSP00000361137.4
VEGFA	ENST00000476772.5	n.-116A>C		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0455 AC: 6899 AN: 151746 Hom.: 235 Cov.: 33

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00661

Gnomad AMR AF: 0.0409

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.130

Gnomad SAS AF: 0.0558

Gnomad FIN AF: 0.0648

Gnomad MID AF: 0.0382

Gnomad NFE AF: 0.0597

Gnomad OTH AF: 0.0470

GnomAD4 exome AF: 0.0447 AC: 6342 AN: 141776 Hom.: 183 AF XY: 0.0442 AC XY: 3079 AN XY: 69732

Gnomad4 AFR exome AF: 0.00902

Gnomad4 AMR exome AF: 0.0268

Gnomad4 ASJ exome AF: 0.0165

Gnomad4 EAS exome AF: 0.0476

Gnomad4 SAS exome AF: 0.0361

Gnomad4 FIN exome AF: 0.0503

Gnomad4 NFE exome AF: 0.0489

Gnomad4 OTH exome AF: 0.0426

GnomAD4 genome AF: 0.0454 AC: 6894 AN: 151852 Hom.: 235 Cov.: 33 AF XY: 0.0459 AC XY: 3405 AN XY: 74250

Gnomad4 AFR AF: 0.0103

Gnomad4 AMR AF: 0.0410

Gnomad4 ASJ AF: 0.0170

Gnomad4 EAS AF: 0.130

Gnomad4 SAS AF: 0.0548

Gnomad4 FIN AF: 0.0648

Gnomad4 NFE AF: 0.0597

Gnomad4 OTH AF: 0.0471

Alfa AF: 0.0550 Hom.: 46

Bravo AF: 0.0408

Asia WGS AF: 0.0850 AC: 295 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	5.6
DANN	Benign	0.68

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs28357093; hg19: chr6-43737805;