6-43774842-T-C

Variant names:

• chr6-43774842-T-C
• rs833069
• NM_003376.6:c.658+450T>C

Variant summary

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

The NM_003376.6(VEGFA):​c.658+450T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 209,434 control chromosomes in the GnomAD database, including 16,045 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 (13025 hom., cov: 32)
  • Exomes 𝑓: 0.31 (3020 hom.)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.11
• Publications: 80 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.578 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.658+450T>C		intron	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.658+450T>C		intron	N/A	NP_001020537.2	P15692-14
	VEGFA	NM_001025367.3		c.658+450T>C		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.658+450T>C		intron	N/A	ENSP00000500082.3	P15692-13
	VEGFA	ENST00000372055.9	TSL:1	c.658+450T>C		intron	N/A	ENSP00000361125.5	P15692-14
	VEGFA	ENST00000425836.9	TSL:1	c.658+450T>C		intron	N/A	ENSP00000388465.4	A0A0A0MSH5

Frequencies

GnomAD3 genomes AF: 0.396 AC: 60112 AN: 151902 Hom.: 12999 Cov.: 32

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.198

Gnomad AMR AF: 0.385

Gnomad ASJ AF: 0.425

Gnomad EAS AF: 0.413

Gnomad SAS AF: 0.277

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.317

Gnomad OTH AF: 0.419

GnomAD4 exome AF: 0.308 AC: 17709 AN: 57414 Hom.: 3020 Cov.: 0 AF XY: 0.304 AC XY: 9421 AN XY: 30982

African (AFR) AF: 0.570 AC: 1341 AN: 2352

American (AMR) AF: 0.359 AC: 1467 AN: 4090

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 618 AN: 1500

East Asian (EAS) AF: 0.400 AC: 1686 AN: 4212

South Asian (SAS) AF: 0.251 AC: 1819 AN: 7248

European-Finnish (FIN) AF: 0.209 AC: 418 AN: 1998

Middle Eastern (MID) AF: 0.367 AC: 66 AN: 180

European-Non Finnish (NFE) AF: 0.286 AC: 9456 AN: 33036

Other (OTH) AF: 0.299 AC: 838 AN: 2798

GnomAD4 genome AF: 0.396 AC: 60194 AN: 152020 Hom.: 13025 Cov.: 32 AF XY: 0.391 AC XY: 29076 AN XY: 74312

African (AFR) AF: 0.584 AC: 24180 AN: 41428

American (AMR) AF: 0.385 AC: 5884 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.425 AC: 1477 AN: 3472

East Asian (EAS) AF: 0.413 AC: 2135 AN: 5164

South Asian (SAS) AF: 0.277 AC: 1334 AN: 4822

European-Finnish (FIN) AF: 0.232 AC: 2453 AN: 10576

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.317 AC: 21536 AN: 67956

Other (OTH) AF: 0.420 AC: 887 AN: 2112

Alfa AF: 0.357 Hom.: 26389

Bravo AF: 0.422

Asia WGS AF: 0.339 AC: 1177 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.70
PhyloP100		-2.1
PromoterAI		0.048	Neutral
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: rs833069; hg19: chr6-43742579;