ARHGDIA
protein-codingRho GDP dissociation inhibitor alpha
Gene summary
This gene encodes a protein that plays a key role in the regulation of signaling through Rho GTPases. The encoded protein inhibits the disassociation of Rho family members from GDP (guanine diphosphate), thereby maintaining these factors in an inactive state. Activity of this protein is important in a variety of cellular processes, and expression of this gene may be altered in tumors. Mutations in this gene have been found in individuals with nephrotic syndrome, type 8. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]
- GDIA1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0014099
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014099
Submitter: ClinGen
The relationship between ARHGDIA (Rho-GDP dissociation inhibitor alpha) and AR Nephrotic syndrome type 8 was evaluated using the ClinGen Clinical Validity Framework. The ARHGDIA gene encodes a protein that regulates signalling through the Rho GTPases that are also critical for the functioning of the actin cytoskeleton. ARHGDIA inhibits the dissociation of the Rho family members from GDP and keeps them in an inactive state. It is expressed ubiquitously but at high levels in the kidney, lung, thymus, spleen and small intestine. ARHGDIA was first reported in relation to nephrotic syndrome by Gupta in 2013 (PMID: 23434736) and by Gee (PMID: 238675020) in 2013 independently. This is the only disease associated with pathogenic variants in this gene. The clinical presentation is with the nephrotic syndrome soon after birth. Only three pathogenic variants have been reported in ARHGDIA associated with human disease. These are a missense variant, an amino acid deletion and a truncating variant. The mechanism of pathogenicity is Gain of Function. However the gene-disease association is supported by experimental expression, protein interaction data, functional alterations in patient and non-patient cells and in non-human model organisms. In summary, ARHGDIA is moderately associated with AR nephrotic syndrome. This has been demonstrated in both the clinical diagnostic and research setting, and has been upheld over time. This assessment was performed according to the ClinGen Gene Clinical Validity SOP version 9 and was approved by the Cystic kidney disease and Ciliopathy Working Group on 24 May 2022.
Inheritance Pattern: AD
Disease ID:MONDO:0019006
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014099
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014099
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Renal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
Comments: Renal transplant has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ARHGDIA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004309.6. 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.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 22 | 22 | ||||
| missense | 1 | 34 | 35 | |||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 2 | 0 | 34 | 22 | 0 | 58 |
Highest pathogenic variant AF is 0.0000027368055
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004300.1 | 5 | MANE Select | |
| Ensembl | ENSP00000269321.7 | 5 | MANE Select | |
| RefSeq | NP_001172006.1 | 5 | Standard | |
| RefSeq | NP_001172007.1 | 5 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| arhgdia | Danio rerio | Structure: whole organism Quality: edematous abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Neurotrophin signaling pathway - Homo sapiens (human)
- Vasopressin-regulated water reabsorption - Homo sapiens (human)
- miR-targeted genes in epithelium - TarBase
- miR-targeted genes in leukocytes - TarBase
- miR-targeted genes in lymphocytes - TarBase
Biological Process
- negative regulation of cell adhesion
- Rho protein signal transduction
- regulation of Rho protein signal transduction
- negative regulation of apoptotic process
- positive regulation of GTPase activity
Molecular Function
- Rho GDP-dissociation inhibitor activity
- GTPase activator activity
- protein binding
- Rac GTPase binding
Cellular Component
- cytosol
- cytoskeleton
- membrane
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000269321
- Coding exons
- 5
- Length
- 3686
- Individuals with no LoFs
- 125734
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125740
- p
- 0.0000239
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.20 | 87 | 125 | 0.697 | 0.00000748 | 1329 |
| Missense (PolyPhen) | 23 | 42.853 | 0.53672 | 522 | ||
| Synonymous | -3.35 | 87 | 55.3 | 1.57 | 0.00000374 | 382 |
| Loss of Function | 1.86 | 4 | 10.5 | 0.380 | 5.75e-7 | 117 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0.00010 | 0.000099 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0.000046 | 0.000046 | rare |
| European (Non-Finnish) | 0.0000088 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Controls Rho proteins homeostasis. Regulates the GDP/GTP exchange reaction of the Rho proteins by inhibiting the dissociation of GDP from them, and the subsequent binding of GTP to them. Retains Rho proteins such as CDC42, RAC1 and RHOA in an inactive cytosolic pool, regulating their stability and protecting them from degradation. Actively involved in the recycling and distribution of activated Rho GTPases in the cell, mediates extraction from membranes of both inactive and activated molecules due its exceptionally high affinity for prenylated forms. Through the modulation of Rho proteins, may play a role in cell motility regulation. In glioma cells, inhibits cell migration and invasion by mediating the signals of SEMA5A and PLXNB3 that lead to inactivation of RAC1. {ECO:0000269|PubMed:20400958, ECO:0000269|PubMed:23434736}.;
- Disease
- DISEASE: Nephrotic syndrome 8 (NPHS8) [MIM:615244]: A form of nephrotic syndrome, a renal disease clinically characterized by progressive renal failure, severe proteinuria, hypoalbuminemia, hyperlipidemia and edema. Kidney biopsies show diffuse mesangial sclerosis, with small glomeruli, hypercellularity, increased extracellular matrix, and contracted/collapsed glomerular tufts surrounded by immature or abnormal podocytes. {ECO:0000269|PubMed:23434736}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Intolerance Scores
- LoFtool
- 0.222
- RVIS EVS
- -0.25
- RVIS percentile EVS
- 35.42
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.973
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |