rs3025006

Variant names:

• chr6-43779511-C-T
• rs3025006
• NM_003376.6:c.962+593C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001025366.3(VEGFA):​c.962+593C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.385 in 375,046 control chromosomes in the GnomAD database, including 28,728 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 0.40 (12356 hom., cov: 31)
  • Exomes 𝑓: 0.37 (16372 hom.)
• Consequence: VEGFA NM_001025366.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.116
• Publications: 8 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025366.3. 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.962+593C>T		intron	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.962+593C>T		intron	N/A	NP_001020537.2
	VEGFA	NM_001025367.3		c.962+593C>T		intron	N/A	NP_001020538.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VEGFA	ENST00000672860.3	MANE Select	c.962+593C>T		intron	N/A	ENSP00000500082.3
	VEGFA	ENST00000372055.9	TSL:1	c.962+593C>T		intron	N/A	ENSP00000361125.5
	VEGFA	ENST00000425836.9	TSL:1	c.962+593C>T		intron	N/A	ENSP00000388465.4

Frequencies

GnomAD3 genomes AF: 0.400 AC: 60779 AN: 151772 Hom.: 12339 Cov.: 31

Gnomad AFR AF: 0.464

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.400

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.535

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.418

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.420

GnomAD4 exome AF: 0.375 AC: 83674 AN: 223156 Hom.: 16372 Cov.: 0 AF XY: 0.369 AC XY: 44875 AN XY: 121516

African (AFR) AF: 0.473 AC: 2824 AN: 5972

American (AMR) AF: 0.390 AC: 4898 AN: 12572

Ashkenazi Jewish (ASJ) AF: 0.461 AC: 2416 AN: 5244

East Asian (EAS) AF: 0.522 AC: 5855 AN: 11216

South Asian (SAS) AF: 0.320 AC: 13007 AN: 40592

European-Finnish (FIN) AF: 0.303 AC: 3800 AN: 12528

Middle Eastern (MID) AF: 0.434 AC: 408 AN: 940

European-Non Finnish (NFE) AF: 0.376 AC: 46283 AN: 123002

Other (OTH) AF: 0.377 AC: 4183 AN: 11090

GnomAD4 genome AF: 0.401 AC: 60832 AN: 151890 Hom.: 12356 Cov.: 31 AF XY: 0.396 AC XY: 29408 AN XY: 74240

African (AFR) AF: 0.464 AC: 19229 AN: 41414

American (AMR) AF: 0.400 AC: 6112 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1540 AN: 3470

East Asian (EAS) AF: 0.536 AC: 2761 AN: 5154

South Asian (SAS) AF: 0.318 AC: 1530 AN: 4810

European-Finnish (FIN) AF: 0.297 AC: 3128 AN: 10538

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.373 AC: 25318 AN: 67912

Other (OTH) AF: 0.423 AC: 891 AN: 2108

Alfa AF: 0.393 Hom.: 11426

Bravo AF: 0.416

Asia WGS AF: 0.402 AC: 1396 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.3
DANN	Benign	0.78
PhyloP100		-0.12
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: rs3025006; hg19: chr6-43747248;