rs1570360

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 494 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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

African (AFR) AF: 0.920 AC: 4446 AN: 4832

American (AMR) AF: 0.754 AC: 2874 AN: 3812

Ashkenazi Jewish (ASJ) AF: 0.706 AC: 4561 AN: 6458

East Asian (EAS) AF: 0.854 AC: 14611 AN: 17112

South Asian (SAS) AF: 0.696 AC: 841 AN: 1208

European-Finnish (FIN) AF: 0.634 AC: 5204 AN: 8210

Middle Eastern (MID) AF: 0.729 AC: 548 AN: 752

European-Non Finnish (NFE) AF: 0.669 AC: 58705 AN: 87710

Other (OTH) AF: 0.717 AC: 6963 AN: 9710

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

African (AFR) AF: 0.920 AC: 38163 AN: 41478

American (AMR) AF: 0.782 AC: 11953 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.702 AC: 2430 AN: 3464

East Asian (EAS) AF: 0.821 AC: 4190 AN: 5102

South Asian (SAS) AF: 0.705 AC: 3394 AN: 4814

European-Finnish (FIN) AF: 0.635 AC: 6700 AN: 10558

Middle Eastern (MID) AF: 0.692 AC: 202 AN: 292

European-Non Finnish (NFE) AF: 0.674 AC: 45681 AN: 67810

Other (OTH) AF: 0.758 AC: 1597 AN: 2106

Alfa AF: 0.697 Hom.: 34328

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
PhyloP100		-0.28
PromoterAI		-0.12	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs1570360; hg19: chr6-43737830;