6-43777358-C-A

Variant names:

• chr6-43777358-C-A
• rs2146323
• NM_003376.6:c.659-111C>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.659-111C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.338 in 1,249,802 control chromosomes in the GnomAD database, including 72,912 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 0.31 (7443 hom., cov: 33)
  • Exomes 𝑓: 0.34 (65469 hom.)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.493
• Publications: 90 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=-0.65).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.393 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.659-111C>A		intron	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.659-111C>A		intron	N/A	NP_001020537.2	P15692-14
	VEGFA	NM_001025367.3		c.659-111C>A		intron	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.659-111C>A		intron	N/A	ENSP00000500082.3	P15692-13
	VEGFA	ENST00000372055.9	TSL:1	c.659-111C>A		intron	N/A	ENSP00000361125.5	P15692-14
	VEGFA	ENST00000425836.9	TSL:1	c.659-111C>A		intron	N/A	ENSP00000388465.4	A0A0A0MSH5

Frequencies

GnomAD3 genomes AF: 0.311 AC: 47270 AN: 152024 Hom.: 7441 Cov.: 33

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.406

Gnomad FIN AF: 0.388

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.298

GnomAD4 exome AF: 0.342 AC: 375654 AN: 1097660 Hom.: 65469 Cov.: 15 AF XY: 0.345 AC XY: 192426 AN XY: 557896

African (AFR) AF: 0.214 AC: 5653 AN: 26366

American (AMR) AF: 0.336 AC: 12979 AN: 38674

Ashkenazi Jewish (ASJ) AF: 0.296 AC: 6996 AN: 23602

East Asian (EAS) AF: 0.277 AC: 10050 AN: 36312

South Asian (SAS) AF: 0.410 AC: 30874 AN: 75286

European-Finnish (FIN) AF: 0.383 AC: 15957 AN: 41628

Middle Eastern (MID) AF: 0.333 AC: 1193 AN: 3582

European-Non Finnish (NFE) AF: 0.343 AC: 275744 AN: 804054

Other (OTH) AF: 0.337 AC: 16208 AN: 48156

GnomAD4 genome AF: 0.311 AC: 47300 AN: 152142 Hom.: 7443 Cov.: 33 AF XY: 0.315 AC XY: 23458 AN XY: 74374

African (AFR) AF: 0.219 AC: 9082 AN: 41494

American (AMR) AF: 0.316 AC: 4827 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1057 AN: 3470

East Asian (EAS) AF: 0.262 AC: 1356 AN: 5174

South Asian (SAS) AF: 0.408 AC: 1968 AN: 4826

European-Finnish (FIN) AF: 0.388 AC: 4101 AN: 10574

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23786 AN: 68008

Other (OTH) AF: 0.298 AC: 628 AN: 2106

Alfa AF: 0.323 Hom.: 15792

Bravo AF: 0.296

Asia WGS AF: 0.370 AC: 1283 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	11
DANN	Benign	0.85
PhyloP100		0.49
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs2146323; hg19: chr6-43745095;