VEGFA

protein-coding

vascular endothelial growth factor A, the group of VEGF family

Gene summary

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]

Previous symbols:
  • VEGF

MANE transcript

NM_003376.6

Inheritance

AD

ClinVar variants

P:2U:65B:18

Top phenotype

Prostate cancer, hereditary, 1

gnomAD constraint

pLI —, LoF o/e 0.51

Max pathogenic AF

—

Genomic locus

chr6:43,770,184-43,786,487

External References & Databases

Transcript & Mutation Effects

hg38 • Region Span ~16.3 kb
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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*VEGFA* was first reported in relation to autosomal dominant congenital heart disease in 2010 (Zhao et al., PMID: 20420808). Six variants (missense, frameshift, nonsense) that have been reported in six probands in four publications (PMIDs: 20420808, 22067973, 29261186, 30232381) are included in this curation, but only one variant (nonsense) was scored, as the other variants were present in unaffected family members and/or too frequent in population databases. The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (NCBI fetal expression data). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date May 7th, 2024 (SOP Version 10).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to VEGFA variants in ClinVar

5 Conditions Cataloged
not specifiedTotal: 49
not providedTotal: 14
Prostate cancer, hereditary, 1Total: 10
VEGFA-related disorderTotal: 7
Microvascular complications of diabetes, susceptibility to, 1Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003376.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
9
clinvar
1
clinvar
10
missense
52
clinvar
8
clinvar
60
nonsense
1
clinvar
1
start loss
0
frameshift
2
clinvar
8
clinvar
10
splice donor/acceptor (+/-2bp)
4
clinvar
4
Total026517185

Highest pathogenic variant AF is 0.000016765995

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_003376.6RefSeqNP_003367.48MANE Select
ENST00000672860.3EnsemblENSP00000500082.38MANE Select
NM_001025366.3RefSeqNP_001020537.28Standard
NM_001025367.3RefSeqNP_001020538.28Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
vegfaaDanio rerio

Structure: blood vessel endothelial cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • PI3K-Akt signaling pathway - Homo sapiens (human)
  • Focal adhesion - Homo sapiens (human)
  • Relaxin signaling pathway - Homo sapiens (human)
  • Kaposi,s sarcoma-associated herpesvirus infection - Homo sapiens (human)
  • Renal cell carcinoma - Homo sapiens (human)

Biological Process

  • negative regulation of transcription by RNA polymerase II
  • angiogenesis
  • ovarian follicle development
  • branching involved in blood vessel morphogenesis
  • vasculogenesis

Molecular Function

  • fibronectin binding
  • cytokine activity
  • platelet-derived growth factor receptor binding
  • vascular endothelial growth factor receptor binding
  • protein binding

Cellular Component

  • extracellular region
  • extracellular space
  • cytoplasm
  • cell surface
  • membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000372055
Coding exons
8
Length
16304
Individuals with no LoFs
125716
Homozygous LoFs
0
Heterozygous LoFs
32
Defined
125748
p
0.000127
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.4672032230.9120.00001302628
Missense (PolyPhen)4566.2130.67962747
Synonymous-0.8199989.21.110.00000528827
Loss of Function2.121121.70.5080.00000119243

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.0000470.000046rare
European (Non-Finnish)0.000250.00025rare
South Asian0.0000330.000033rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Growth factor active in angiogenesis, vasculogenesis and endothelial cell growth. Induces endothelial cell proliferation, promotes cell migration, inhibits apoptosis and induces permeabilization of blood vessels. Binds to the FLT1/VEGFR1 and KDR/VEGFR2 receptors, heparan sulfate and heparin. NRP1/Neuropilin-1 binds isoforms VEGF-165 and VEGF-145. Isoform VEGF165B binds to KDR but does not activate downstream signaling pathways, does not activate angiogenesis and inhibits tumor growth. Binding to NRP1 receptor initiates a signaling pathway needed for motor neuron axon guidance and cell body migration, including for the caudal migration of facial motor neurons from rhombomere 4 to rhombomere 6 during embryonic development (By similarity). {ECO:0000250|UniProtKB:Q00731, ECO:0000269|PubMed:11427521, ECO:0000269|PubMed:16489009}.;
Disease
DISEASE: Microvascular complications of diabetes 1 (MVCD1) [MIM:603933]: Pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end- stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis. {ECO:0000269|PubMed:11978667}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0942

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.792

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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