FGD4

protein-coding

FYVE, RhoGEF and PH domain containing 4, the group of Pleckstrin homology domain containing|Zinc fingers FYVE-type|Dbl family Rho GEFs

Gene summary

This gene encodes a protein that is involved in the regulation of the actin cytoskeleton and cell shape. This protein contains an actin filament-binding domain, which together with its Dbl homology domain and one of its pleckstrin homology domains, can form microspikes. This protein can activate MAPK8 independently of the actin filament-binding domain, and it is also involved in the activation of CDC42 via the exchange of bound GDP for free GTP. The activation of CDC42 also enables this protein to play a role in mediating the cellular invasion of Cryptosporidium parvum, an intracellular parasite that infects the gastrointestinal tract. Mutations in this gene can cause Charcot-Marie-Tooth disease type 4H (CMT4H), a disorder of the peripheral nervous system. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2015]

MANE transcript

NM_001370298.3

Inheritance

ClinVar variants

P:59U:294B:146

Top phenotype

Charcot-Marie-Tooth disease, demyelinating, type 4H

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr12:32,399,558-32,646,050

External References & Databases

Ensembl (ENSG00000139132)

Transcript & Mutation Effects

hg38 • Region Span ~246.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease type 4HSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012250

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease type 4HSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012250

Submitter: PanelApp Australia

Charcot-Marie-Tooth diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015626

Submitter: ClinGen

FGD4 was first reported in relation to autosomal recessive Charcot-Marie-Tooth Disease in 2005 (De Sandre-Giovannoli et al., PMID: 15744041), and variant(s) in this gene were associated with Charcot-Marie-Tooth disease in 2007 (Delague et al., 2007; PMID:17564959).Reported cases to date have a childhood onset and are further characterized by very slow motor conduction velocities, and nerve biopsies that show conspicuously folded myelin sheaths. At least 32 unique variants, including missense, nonsense, splice, frameshift, and indels have been reported in humans (Delague et al., 2007; PMID:17564959, Stendel et al., 2007; PMID:17564972, databases the Inherited Neuropathy Variant Database, LOVD, and HGMD) This gene-disease relationship is supported by expression studies and animal models. Investigation determined that FGD4 is ubiquitously expressed in human tissue, and was found to have the highest levels of expression in mouse nerve tissue during the embryonic stage. Additionally, mice with a disruption of FGD4 were found to have dysmyelination in early nerve development and additional myelin abnormalities at later stages of development. Frabin is a guanine nucleotide exchange factor for CDC42, and deleting Fdg4 or Cdc42 in Schwann cells results in a similar defect in myelination, showing that these two genes have an essential function in myelinating Schwann cells. In transfected cells, C-terminal truncations of frabin result in fewer microspikes, which could be a biological assay for investigating FDG4 variants. In summary, FGD4 is DEFINITIVELY associated with autosomal recessive Charcot-Marie-Tooth Disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Charcot-Marie-Tooth disease type 4HSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012250

Submitter: Orphanet

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth disease, demyelinating, type 4HAR

Manifestation: 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

Refs: 15744041; 17564959; 17564972; 19221294; 19332693; 20301641; 21840889; 22734899

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FGD4 variants in ClinVar

8 Conditions Cataloged

Charcot-Marie-Tooth disease type 4Total: 461

not providedTotal: 135

Inborn genetic diseasesTotal: 126

Charcot-Marie-Tooth disease type 4HTotal: 96

FGD4-related disorderTotal: 48

not specifiedTotal: 46

Charcot-Marie-Tooth diseaseTotal: 46

Charcot-Marie-Tooth disease type 4ATotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001370298.3. 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			6 clinvar	128 clinvar	3 clinvar	137
missense	1 clinvar	2 clinvar	274 clinvar	14 clinvar	1 clinvar	292
nonsense	13 clinvar	5 clinvar	2 clinvar			20
start loss						0
frameshift	22 clinvar	11 clinvar	6 clinvar			39
splice donor/acceptor (+/-2bp)		5 clinvar	6 clinvar			11
Total	36	23	294	142	4	499

Highest pathogenic variant AF is 0.000023658236

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001370298.3	RefSeq	NP_001357227.2	17	MANE Select
ENST00000534526.7	Ensembl	ENSP00000449273.1	17	MANE Select
NM_001304481.2	RefSeq	NP_001291410.1	17	Standard
NM_001304483.2	RefSeq	NP_001291412.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glucocorticoid Receptor Pathway
Nuclear Receptors Meta-Pathway
Signaling by GPCR
Signal Transduction
Rho GTPase cycle

Biological Process

cytoskeleton organization
G protein-coupled receptor signaling pathway
regulation of cell shape
actin cytoskeleton organization
regulation of Rho protein signal transduction

Molecular Function

actin binding
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: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000427716
Coding exons: 15
Length: 246522
Individuals with no LoFs: 125709
Homozygous LoFs: 0
Heterozygous LoFs: 39
Defined: 125748
p: 0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.14	275	395	0.696	0.0000193	5064
Missense (PolyPhen)		56	116.96	0.47878		1508
Synonymous	0.580	126	135	0.936	0.00000637	1410
Loss of Function	4.30	12	42.1	0.285	0.00000238	502

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00011	0.00011	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00033	0.00033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

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. Activates MAPK8 (By similarity). {ECO:0000250, ECO:0000269|PubMed:15133042}.;
Disease: DISEASE: Charcot-Marie-Tooth disease 4H (CMT4H) [MIM:609311]: A recessive demyelinating form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot- Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Demyelinating neuropathies are characterized by severely reduced nerve conduction velocities (less than 38 m/sec), segmental demyelination and remyelination with onion bulb formations on nerve biopsy, slowly progressive distal muscle atrophy and weakness, absent deep tendon reflexes, and hollow feet. By convention autosomal recessive forms of demyelinating Charcot-Marie-Tooth disease are designated CMT4. {ECO:0000269|PubMed:17564959, ECO:0000269|PubMed:17564972}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.130

Intolerance Scores

LoFtool: 0.683
RVIS EVS: -0.16
RVIS percentile EVS: 42.16

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0794

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	High	Medium	High
Cancer	High	High	High