6-43770172-C-A

Variant names:

• chr6-43770172-C-A
• rs36208384
• NM_003376.6:c.-535C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003376.6(VEGFA):​c.-535C>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0092 in 253,558 control chromosomes in the GnomAD database, including 18 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 0.0090 (9 hom., cov: 31)
  • Exomes 𝑓: 0.0095 (9 hom.)
• Consequence: VEGFA NM_003376.6 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.725
• Publications: 3 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BS2: High AC in GnomAd4 at 1365 AD gene.

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.-535C>A		upstream_gene	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.-535C>A		upstream_gene	N/A	NP_001020537.2	P15692-14
	VEGFA	NM_001025367.3		c.-535C>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.-535C>A		upstream_gene	N/A	ENSP00000500082.3	P15692-13
	VEGFA	ENST00000425836.9	TSL:1	c.-535C>A		upstream_gene	N/A	ENSP00000388465.4	A0A0A0MSH5
	VEGFA	ENST00000372067.8	TSL:1	c.-535C>A		upstream_gene	N/A	ENSP00000361137.4	P15692-11

Frequencies

GnomAD3 genomes AF: 0.00902 AC: 1367 AN: 151512 Hom.: 9 Cov.: 31

Gnomad AFR AF: 0.00269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00459

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00396

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0140

Gnomad OTH AF: 0.00529

GnomAD4 exome AF: 0.00951 AC: 969 AN: 101936 Hom.: 9 Cov.: 0 AF XY: 0.00919 AC XY: 449 AN XY: 48864

African (AFR) AF: 0.00222 AC: 9 AN: 4060

American (AMR) AF: 0.00605 AC: 17 AN: 2808

Ashkenazi Jewish (ASJ) AF: 0.00237 AC: 13 AN: 5492

East Asian (EAS) AF: 0.000592 AC: 8 AN: 13510

South Asian (SAS) AF: 0.00112 AC: 1 AN: 890

European-Finnish (FIN) AF: 0.0158 AC: 49 AN: 3110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 604

European-Non Finnish (NFE) AF: 0.0124 AC: 794 AN: 63786

Other (OTH) AF: 0.0102 AC: 78 AN: 7676

GnomAD4 genome AF: 0.00900 AC: 1365 AN: 151622 Hom.: 9 Cov.: 31 AF XY: 0.00874 AC XY: 648 AN XY: 74108

African (AFR) AF: 0.00268 AC: 111 AN: 41408

American (AMR) AF: 0.00452 AC: 69 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5070

South Asian (SAS) AF: 0.00396 AC: 19 AN: 4796

European-Finnish (FIN) AF: 0.0187 AC: 197 AN: 10522

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.0140 AC: 951 AN: 67772

Other (OTH) AF: 0.00523 AC: 11 AN: 2102

Alfa AF: 0.00242 Hom.: 0

Bravo AF: 0.00789

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	5.5
DANN	Benign	0.53
PhyloP100		-0.72
PromoterAI		-0.26	Neutral

Splicing

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

Other links and lift over

dbSNP: rs36208384; hg19: chr6-43737909;