6-43770037-C-A

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 10 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]

VEGFA Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	NM_003376.6	MANE Select	c.-670C>A		upstream_gene	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.-670C>A		upstream_gene	N/A	NP_001020537.2	P15692-14
	VEGFA	NM_001025367.3		c.-670C>A		upstream_gene	N/A	NP_001020538.2	P15692-16

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	ENST00000672860.3	MANE Select	c.-670C>A		upstream_gene	N/A	ENSP00000500082.3	P15692-13
	VEGFA	ENST00000425836.9	TSL:1	c.-670C>A		upstream_gene	N/A	ENSP00000388465.4	A0A0A0MSH5
	VEGFA	ENST00000372067.8	TSL:1	c.-670C>A		upstream_gene	N/A	ENSP00000361137.4	P15692-11

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

African (AFR) AF: 0.112 AC: 519 AN: 4654

American (AMR) AF: 0.0190 AC: 70 AN: 3692

Ashkenazi Jewish (ASJ) AF: 0.00126 AC: 8 AN: 6356

East Asian (EAS) AF: 0.0000605 AC: 1 AN: 16516

South Asian (SAS) AF: 0.000890 AC: 1 AN: 1124

European-Finnish (FIN) AF: 0.000121 AC: 1 AN: 8242

Middle Eastern (MID) AF: 0.0137 AC: 10 AN: 732

European-Non Finnish (NFE) AF: 0.00200 AC: 171 AN: 85654

Other (OTH) AF: 0.0158 AC: 150 AN: 9516

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

African (AFR) AF: 0.127 AC: 5277 AN: 41510

American (AMR) AF: 0.0222 AC: 339 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.00209 AC: 142 AN: 67992

Other (OTH) AF: 0.0351 AC: 74 AN: 2110

Alfa AF: 0.00792 Hom.: 10

Bravo AF: 0.0442

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.6
DANN	Benign	0.86
PhyloP100		-1.8
PromoterAI		-0.13	Neutral

Splicing

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

Other links and lift over

dbSNP: rs59260042; hg19: chr6-43737774;