chr6-43770057-A-G

Variant names:

• chr6-43770057-A-G
• rs13207351
• NM_003376.6:c.-650A>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.-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

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 6-43770057-A-G is Benign according to our data. Variant chr6-43770057-A-G is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.-650A>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.-650A>G		upstream_gene_variant			NM_003376.6	ENSP00000500082.3
VEGFA	ENST00000425836.9	c.-650A>G		upstream_gene_variant		1		ENSP00000388465.4
VEGFA	ENST00000372067.8	c.-650A>G		upstream_gene_variant		1		ENSP00000361137.4
VEGFA	ENST00000476772.5	n.-127A>G		upstream_gene_variant		1

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

Gnomad4 AFR exome AF: 0.726

Gnomad4 AMR exome AF: 0.588

Gnomad4 ASJ exome AF: 0.540

Gnomad4 EAS exome AF: 0.692

Gnomad4 SAS exome AF: 0.537

Gnomad4 FIN exome AF: 0.424

Gnomad4 NFE exome AF: 0.490

Gnomad4 OTH exome AF: 0.541

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

Gnomad4 AFR AF: 0.735

Gnomad4 AMR AF: 0.607

Gnomad4 ASJ AF: 0.548

Gnomad4 EAS AF: 0.725

Gnomad4 SAS AF: 0.551

Gnomad4 FIN AF: 0.448

Gnomad4 NFE AF: 0.502

Gnomad4 OTH AF: 0.613

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	6.0
DANN	Benign	0.47

Splicing

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

Publications

LitVar

Other links and lift over

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