rs3025015

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003376.6(VEGFA):​c.963-119G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0506 in 1,459,574 control chromosomes in the GnomAD database, including 2,180 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 0.044 ( 194 hom., cov: 33)
Exomes 𝑓: 0.051 ( 1986 hom. )

Consequence

VEGFA
NM_003376.6 intron

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.882
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.93).
BA1
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.074 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
VEGFANM_003376.6 linkuse as main transcriptc.963-119G>A intron_variant ENST00000672860.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
VEGFAENST00000672860.3 linkuse as main transcriptc.963-119G>A intron_variant NM_003376.6 P15692-13

Frequencies

GnomAD3 genomes
AF:
0.0438
AC:
6656
AN:
152102
Hom.:
193
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0165
Gnomad AMI
AF:
0.0175
Gnomad AMR
AF:
0.0367
Gnomad ASJ
AF:
0.0161
Gnomad EAS
AF:
0.0802
Gnomad SAS
AF:
0.0629
Gnomad FIN
AF:
0.0719
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.0555
Gnomad OTH
AF:
0.0377
GnomAD4 exome
AF:
0.0513
AC:
67118
AN:
1307354
Hom.:
1986
Cov.:
19
AF XY:
0.0516
AC XY:
33620
AN XY:
651816
show subpopulations
Gnomad4 AFR exome
AF:
0.0131
Gnomad4 AMR exome
AF:
0.0236
Gnomad4 ASJ exome
AF:
0.0155
Gnomad4 EAS exome
AF:
0.0417
Gnomad4 SAS exome
AF:
0.0579
Gnomad4 FIN exome
AF:
0.0662
Gnomad4 NFE exome
AF:
0.0541
Gnomad4 OTH exome
AF:
0.0457
GnomAD4 genome
AF:
0.0438
AC:
6664
AN:
152220
Hom.:
194
Cov.:
33
AF XY:
0.0444
AC XY:
3305
AN XY:
74412
show subpopulations
Gnomad4 AFR
AF:
0.0165
Gnomad4 AMR
AF:
0.0368
Gnomad4 ASJ
AF:
0.0161
Gnomad4 EAS
AF:
0.0804
Gnomad4 SAS
AF:
0.0627
Gnomad4 FIN
AF:
0.0719
Gnomad4 NFE
AF:
0.0555
Gnomad4 OTH
AF:
0.0406
Alfa
AF:
0.0502
Hom.:
156
Bravo
AF:
0.0384
Asia WGS
AF:
0.0690
AC:
238
AN:
3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.93
CADD
Benign
1.6
DANN
Benign
0.65

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs3025015; hg19: chr6-43748350; API