FGD1
protein-codingFYVE, RhoGEF and PH domain containing 1, the group of Dbl family Rho GEFs|Zinc fingers FYVE-type|Pleckstrin homology domain containing
Gene summary
This gene encodes a protein that contains Dbl (DH) and pleckstrin (PH) homology domains and is similar to the Rho family of small GTP-binding proteins. The encoded protein specifically binds to the Rho family GTPase Cdc42Hs and can stimulate the GDP-GTP exchange of the isoprenylated form of Cdc42Hs. It also stimulates the mitogen activated protein kinase cascade leading to c-Jun kinase SAPK/JNK1 activation. Defects in this gene are the cause of the faciogenital dysplasia in Aarskog-Scott syndrome and a syndromatic form of X-linked cognitive disability. [provided by RefSeq, Jul 2017]
- FGDY
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~50.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010589
Submitter: ClinGen
*FGD1* was first reported in relation to X-linked Aarskog-Scott syndrome in 1994 (Pasteris et al., PMID: 7954831). *FGD1* encodes a guanine nucleotide exchange factor that activates the Rho GTPase CDC42. CDC42 participates in multiple cellular processes, including cell growth, actin cytoskeleton remodeling, and nuclear signaling. Features seen in affected males include short stature, short and broad hands and feet, genital malformations, and distinctive facial features, including hypertelorism, ptosis, long philtrum, and short nose with anteverted nares. Some individuals have mild intellectual disability or, more commonly, learning difficulties. Female carriers are usually unaffected but may sometimes present with subtle features. Eight variants (nonsense, frameshift, missense, exonic deletion) that have been reported in 11 probands in 8 publications (PMIDs: 7954831, 10930571, 11093277, 14560308, 16353258, 17152066, 20082460, 21739585) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. In summary, there is definitive evidence supporting the relationship between *FGD1* and X-linked Aarskog-Scott syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on December 6, 2017 (SOP Version 5). As of July 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.
Inheritance Pattern: XL
Disease ID:MONDO:0010589
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0010589
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010589
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010589
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Genitourinary; Musculoskeletal; Neurologic
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to FGD1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004463.3. 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 | 15 | 96 | 12 | 123 | ||
| missense | 3 | 18 | 229 | 50 | 3 | 303 |
| nonsense | 10 | 12 | 5 | 27 | ||
| start loss | 1 | 1 | ||||
| frameshift | 28 | 21 | 7 | 56 | ||
| splice donor/acceptor (+/-2bp) | 7 | 9 | 10 | 26 | ||
| Total | 48 | 60 | 267 | 146 | 15 | 536 |
Highest pathogenic variant AF is 0.002493954
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004454.2 | 18 | MANE Select | |
| Ensembl | ENSP00000364277.3 | 18 | MANE Select | |
| Ensembl | ENSP00000604078.1 | 18 | Standard | |
| Ensembl | ENSP00000604078.1 | 18 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Regulation of actin cytoskeleton - Homo sapiens (human)
- Regulation of Actin Cytoskeleton
- Signaling by GPCR
- Signal Transduction
- Rho GTPase cycle
Biological Process
- cytoskeleton organization
- signal transduction
- G protein-coupled receptor signaling pathway
- multicellular organism development
- regulation of cell shape
Molecular Function
- guanyl-nucleotide exchange factor activity
- Rho guanyl-nucleotide exchange factor activity
- small GTPase binding
- metal ion binding
Cellular Component
- ruffle
- cytoplasm
- Golgi apparatus
- cytosol
- cytoskeleton
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000375135
- Coding exons
- 18
- Length
- 50713
- Individuals with no LoFs
- 125679
- Homozygous LoFs
- 2
- Heterozygous LoFs
- 3
- Defined
- 125684
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.52 | 215 | 417 | 0.515 | 0.0000357 | 6169 |
| Missense (PolyPhen) | 40 | 129.7 | 0.30839 | 1847 | ||
| Synonymous | 0.353 | 164 | 170 | 0.966 | 0.0000143 | 2000 |
| Loss of Function | 4.92 | 2 | 32.0 | 0.0624 | 0.00000245 | 505 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000079 | 0.000062 | rare |
| Latino/Admixed American | 0.000037 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0.000064 | 0.000046 | rare |
| European (Non-Finnish) | 0.000012 | 0.0000088 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00023 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Activates CDC42, a member of the Ras-like family of Rho- and Rac proteins, by exchanging bound GDP for free GTP. Plays a role in regulating the actin cytoskeleton and cell shape. {ECO:0000269|PubMed:8969170}.;
- Disease
- DISEASE: Aarskog-Scott syndrome (AAS) [MIM:305400]: An X-linked recessive, rare multisystemic disorder characterized by disproportionately short stature, and by facial, skeletal and urogenital anomalies. Some patients manifest mental retardation, attention deficit disorder and hyperactivity. {ECO:0000269|PubMed:10930571, ECO:0000269|PubMed:11093277, ECO:0000269|PubMed:14560308}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in FGD1 are found in a patient with non- syndromal X-linked mental retardation. {ECO:0000269|PubMed:11940089}.;
Recessive Scores
- pRec
- 0.287
Intolerance Scores
- LoFtool
- 0.132
- RVIS EVS
- -0.51
- RVIS percentile EVS
- 21.56
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.506
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |