rs1570360

Variant names:

• chr6-43770093-A-G
• rs1570360
• NM_003376.6:c.-614A>G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003376.6(VEGFA):​c.-614A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.732 in 291,618 control chromosomes in the GnomAD database, including 79,500 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.76 (44210 hom., cov: 32)
  • Exomes 𝑓: 0.71 (35290 hom.)
• Consequence: VEGFA NM_003376.6 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.275

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-43770093-A-G is Benign according to our data. Variant chr6-43770093-A-G is described in ClinVar as [Benign]. Clinvar id is 1226235.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.-614A>G		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.-614A>G		upstream_gene_variant			NM_003376.6	ENSP00000500082.3
VEGFA	ENST00000425836.9	c.-614A>G		upstream_gene_variant		1		ENSP00000388465.4
VEGFA	ENST00000372067.8	c.-614A>G		upstream_gene_variant		1		ENSP00000361137.4
VEGFA	ENST00000476772.5	n.-91A>G		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.756 AC: 114652 AN: 151704 Hom.: 44151 Cov.: 32

Gnomad AFR AF: 0.920

Gnomad AMI AF: 0.500

Gnomad AMR AF: 0.782

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.821

Gnomad SAS AF: 0.707

Gnomad FIN AF: 0.635

Gnomad MID AF: 0.688

Gnomad NFE AF: 0.674

Gnomad OTH AF: 0.757

GnomAD4 exome AF: 0.706 AC: 98753 AN: 139804 Hom.: 35290 AF XY: 0.703 AC XY: 48389 AN XY: 68808

Gnomad4 AFR exome AF: 0.920

Gnomad4 AMR exome AF: 0.754

Gnomad4 ASJ exome AF: 0.706

Gnomad4 EAS exome AF: 0.854

Gnomad4 SAS exome AF: 0.696

Gnomad4 FIN exome AF: 0.634

Gnomad4 NFE exome AF: 0.669

Gnomad4 OTH exome AF: 0.717

GnomAD4 genome AF: 0.756 AC: 114765 AN: 151814 Hom.: 44210 Cov.: 32 AF XY: 0.755 AC XY: 56029 AN XY: 74190

Gnomad4 AFR AF: 0.920

Gnomad4 AMR AF: 0.782

Gnomad4 ASJ AF: 0.702

Gnomad4 EAS AF: 0.821

Gnomad4 SAS AF: 0.705

Gnomad4 FIN AF: 0.635

Gnomad4 NFE AF: 0.674

Gnomad4 OTH AF: 0.758

Alfa AF: 0.693 Hom.: 29333

Bravo AF: 0.774

Asia WGS AF: 0.789 AC: 2734 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24902660, 23962084, 12067976, 23007030, 11752046, 23404364, 10626738, 21831507) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	9.3
DANN	Benign	0.61

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1570360; hg19: chr6-43737830;