rs3025030

Variant names:

• chr6-43782850-G-C
• rs3025030
• NM_003376.6:c.1166+763G>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.1166+763G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 153,380 control chromosomes in the GnomAD database, including 1,494 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 0.13 (1489 hom., cov: 31)
  • Exomes 𝑓: 0.094 (5 hom.)
• Consequence: VEGFA NM_003376.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.458
• Publications: 40 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.171 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.1166+763G>C		intron	N/A	NP_003367.4
	VEGFA	NM_001025366.3		c.1217+763G>C		intron	N/A	NP_001020537.2	P15692-14
	VEGFA	NM_001025367.3		c.1148+763G>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.1166+763G>C		intron	N/A	ENSP00000500082.3	P15692-13
	VEGFA	ENST00000372055.9	TSL:1	c.1217+763G>C		intron	N/A	ENSP00000361125.5	P15692-14
	VEGFA	ENST00000425836.9	TSL:1	c.1094+763G>C		intron	N/A	ENSP00000388465.4	A0A0A0MSH5

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20232 AN: 151884 Hom.: 1483 Cov.: 31

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.173

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.151

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.139

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.0936 AC: 129 AN: 1378 Hom.: 5 Cov.: 0 AF XY: 0.0966 AC XY: 69 AN XY: 714

African (AFR) AF: 0.00 AC: 0 AN: 10

American (AMR) AF: 0.170 AC: 15 AN: 88

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 3 AN: 22

East Asian (EAS) AF: 0.0476 AC: 2 AN: 42

South Asian (SAS) AF: 0.0750 AC: 3 AN: 40

European-Finnish (FIN) AF: 0.0750 AC: 6 AN: 80

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 6

European-Non Finnish (NFE) AF: 0.0925 AC: 94 AN: 1016

Other (OTH) AF: 0.0811 AC: 6 AN: 74

GnomAD4 genome AF: 0.133 AC: 20270 AN: 152002 Hom.: 1489 Cov.: 31 AF XY: 0.134 AC XY: 9976 AN XY: 74290

African (AFR) AF: 0.104 AC: 4322 AN: 41466

American (AMR) AF: 0.177 AC: 2704 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 452 AN: 3468

East Asian (EAS) AF: 0.173 AC: 894 AN: 5156

South Asian (SAS) AF: 0.101 AC: 486 AN: 4812

European-Finnish (FIN) AF: 0.151 AC: 1591 AN: 10558

Middle Eastern (MID) AF: 0.146 AC: 43 AN: 294

European-Non Finnish (NFE) AF: 0.139 AC: 9435 AN: 67954

Other (OTH) AF: 0.128 AC: 270 AN: 2110

Alfa AF: 0.142 Hom.: 220

Bravo AF: 0.139

Asia WGS AF: 0.143 AC: 497 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.2
DANN	Benign	0.74
PhyloP100		0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs3025030;

hg19: chr6-43750587;