rs59260042

Variant names:

• chr6-43770037-C-A
• rs59260042
• NM_003376.6:c.-670C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-43770037-C-A
• chr6-43770037-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.-670C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 288,680 control chromosomes in the GnomAD database, including 421 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 0.038 (380 hom., cov: 33)
  • Exomes 𝑓: 0.0068 (41 hom.)
• Consequence: VEGFA NM_003376.6 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.78

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=-0.77).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.-670C>A		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.-670C>A		upstream_gene_variant			NM_003376.6	ENSP00000500082.3
VEGFA	ENST00000425836.9	c.-670C>A		upstream_gene_variant		1		ENSP00000388465.4
VEGFA	ENST00000372067.8	c.-670C>A		upstream_gene_variant		1		ENSP00000361137.4
VEGFA	ENST00000476772.5	n.-147C>A		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0384 AC: 5842 AN: 152074 Hom.: 381 Cov.: 33

Gnomad AFR AF: 0.127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0222

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.00209

Gnomad OTH AF: 0.0354

GnomAD4 exome AF: 0.00682 AC: 931 AN: 136486 Hom.: 41 AF XY: 0.00574 AC XY: 385 AN XY: 67058

Gnomad4 AFR exome AF: 0.112

Gnomad4 AMR exome AF: 0.0190

Gnomad4 ASJ exome AF: 0.00126

Gnomad4 EAS exome AF: 0.0000605

Gnomad4 SAS exome AF: 0.000890

Gnomad4 FIN exome AF: 0.000121

Gnomad4 NFE exome AF: 0.00200

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0385 AC: 5853 AN: 152194 Hom.: 380 Cov.: 33 AF XY: 0.0381 AC XY: 2839 AN XY: 74428

Gnomad4 AFR AF: 0.127

Gnomad4 AMR AF: 0.0222

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00209

Gnomad4 OTH AF: 0.0351

Alfa AF: 0.00140 Hom.: 3

Bravo AF: 0.0442

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.6
DANN	Benign	0.86

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs59260042; hg19: chr6-43737774;