6-43770172-C-T

Variant names:

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

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>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 253,562 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00012 (0 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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BS2: High AC in GnomAd4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VEGFA	NM_003376.6	c.-535C>T		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.-535C>T		upstream_gene_variant			NM_003376.6	ENSP00000500082.3
VEGFA	ENST00000425836.9	c.-535C>T		upstream_gene_variant		1		ENSP00000388465.4
VEGFA	ENST00000372067.8	c.-535C>T		upstream_gene_variant		1		ENSP00000361137.4
VEGFA	ENST00000476772.5	n.-12C>T		upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.000198 AC: 30 AN: 151508 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000786

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.000118 AC: 12 AN: 101944 Hom.: 0 Cov.: 0 AF XY: 0.000102 AC XY: 5 AN XY: 48868

African (AFR) AF: 0.00 AC: 0 AN: 4060

American (AMR) AF: 0.000356 AC: 1 AN: 2808

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5492

East Asian (EAS) AF: 0.000444 AC: 6 AN: 13510

South Asian (SAS) AF: 0.00 AC: 0 AN: 890

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3110

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

European-Non Finnish (NFE) AF: 0.0000470 AC: 3 AN: 63792

Other (OTH) AF: 0.000260 AC: 2 AN: 7678

GnomAD4 genome AF: 0.000198 AC: 30 AN: 151618 Hom.: 0 Cov.: 31 AF XY: 0.000202 AC XY: 15 AN XY: 74106

African (AFR) AF: 0.0000724 AC: 3 AN: 41408

American (AMR) AF: 0.000327 AC: 5 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000789 AC: 4 AN: 5070

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4796

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10522

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000148 AC: 10 AN: 67772

Other (OTH) AF: 0.00143 AC: 3 AN: 2102

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.3
DANN	Benign	0.80
PhyloP100		-0.72
PromoterAI		-0.098	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;