6-43770057-A-G

Variant names:

• chr6-43770057-A-G
• rs13207351
• NM_003376.6:c.-650A>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.-650A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.557 in 291,570 control chromosomes in the GnomAD database, including 46,593 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.58 (26554 hom., cov: 32)
  • Exomes 𝑓: 0.53 (20039 hom.)
• Consequence: VEGFA NM_003376.6 upstream_gene
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.171
• Publications: 57 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 6-43770057-A-G is Benign according to our data. Variant chr6-43770057-A-G is described in ClinVar as Benign. ClinVar VariationId is 1245515.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003376.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	NM_003376.6	MANE Select	c.-650A>G		upstream_gene	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.-650A>G		upstream_gene	N/A	NP_001020537.2
	VEGFA	NM_001025367.3		c.-650A>G		upstream_gene	N/A	NP_001020538.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	ENST00000672860.3	MANE Select	c.-650A>G		upstream_gene	N/A	ENSP00000500082.3
	VEGFA	ENST00000425836.9	TSL:1	c.-650A>G		upstream_gene	N/A	ENSP00000388465.4
	VEGFA	ENST00000372067.8	TSL:1	c.-650A>G		upstream_gene	N/A	ENSP00000361137.4

Frequencies

GnomAD3 genomes AF: 0.583 AC: 88483 AN: 151758 Hom.: 26525 Cov.: 32

Gnomad AFR AF: 0.735

Gnomad AMI AF: 0.278

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.548

Gnomad EAS AF: 0.724

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.548

Gnomad NFE AF: 0.503

Gnomad OTH AF: 0.613

GnomAD4 exome AF: 0.528 AC: 73753 AN: 139700 Hom.: 20039 AF XY: 0.525 AC XY: 36048 AN XY: 68666

African (AFR) AF: 0.726 AC: 3448 AN: 4750

American (AMR) AF: 0.588 AC: 2237 AN: 3802

Ashkenazi Jewish (ASJ) AF: 0.540 AC: 3475 AN: 6432

East Asian (EAS) AF: 0.692 AC: 11687 AN: 16886

South Asian (SAS) AF: 0.537 AC: 634 AN: 1180

European-Finnish (FIN) AF: 0.424 AC: 3633 AN: 8576

Middle Eastern (MID) AF: 0.596 AC: 434 AN: 728

European-Non Finnish (NFE) AF: 0.490 AC: 42927 AN: 87592

Other (OTH) AF: 0.541 AC: 5278 AN: 9754

GnomAD4 genome AF: 0.583 AC: 88568 AN: 151870 Hom.: 26554 Cov.: 32 AF XY: 0.582 AC XY: 43187 AN XY: 74200

African (AFR) AF: 0.735 AC: 30495 AN: 41468

American (AMR) AF: 0.607 AC: 9276 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 1898 AN: 3466

East Asian (EAS) AF: 0.725 AC: 3712 AN: 5120

South Asian (SAS) AF: 0.551 AC: 2656 AN: 4816

European-Finnish (FIN) AF: 0.448 AC: 4718 AN: 10530

Middle Eastern (MID) AF: 0.565 AC: 165 AN: 292

European-Non Finnish (NFE) AF: 0.502 AC: 34107 AN: 67876

Other (OTH) AF: 0.613 AC: 1289 AN: 2102

Alfa AF: 0.358 Hom.: 831

Bravo AF: 0.605

Asia WGS AF: 0.606 AC: 2099 AN: 3466

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.0
DANN	Benign	0.47
PhyloP100		-0.17
PromoterAI		0.011	Neutral

Splicing

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

Other links and lift over

dbSNP: rs13207351; hg19: chr6-43737794; COSMIC: COSV57878443;