FGD4

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

Basic information

Region (hg38): 12:32399558-32646050

Links

ENSG00000139132 ∙ NCBI:121512 ∙ OMIM:611104 ∙ HGNC:19125 ∙ Uniprot:Q96M96 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Charcot-Marie-Tooth disease type 4H (Strong), mode of inheritance: AR
• Charcot-Marie-Tooth disease type 4H (Supportive), mode of inheritance: AR
• Charcot-Marie-Tooth disease (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Charcot-Marie-Tooth disease, type 4H	AR	General	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	Neurologic	15744041; 17564959; 17564972; 19221294; 19332693; 20301641; 21840889; 22734899

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FGD4 gene.

• Charcot-Marie-Tooth disease type 4 (23 variants)
• not provided (5 variants)
• Charcot-Marie-Tooth disease type 4H (5 variants)
• Charcot-Marie-Tooth disease (2 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FGD4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			1	101	5	107
missense	1		226	6	2	235
nonsense	12	2	1			15
start loss						0
frameshift	14	5	2			21
inframe indel			7			7
splice donor/acceptor (+/-2bp)		3	2	1		6
splice region		1	14	20	3	38
non coding			84	90	88	262
Total	27	10	323	198	95

Highest pathogenic variant AF is 0.0000329

Variants in FGD4

This is a list of pathogenic ClinVar variants found in the FGD4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
12-32399835-C-G		Charcot-Marie-Tooth disease type 4H	Benign (Aug 10, 2021)
12-32399960-G-A		not specified	Uncertain significance (Aug 26, 2022)
12-32486135-TG-T		Charcot-Marie-Tooth disease type 4H	Uncertain significance (Aug 07, 2018)
12-32502100-C-A		Charcot-Marie-Tooth disease type 4	Likely benign (Jun 14, 2016)
12-32502129-C-A		Charcot-Marie-Tooth disease type 4H	Uncertain significance (Apr 27, 2017)
12-32502136-C-G		Charcot-Marie-Tooth disease type 4H	Uncertain significance (Jan 13, 2018)
12-32502137-T-C		Charcot-Marie-Tooth disease type 4H	Uncertain significance (Jan 12, 2018)
12-32502151-C-G		Charcot-Marie-Tooth disease type 4H	Uncertain significance (Jan 13, 2018)
12-32502151-C-T		Charcot-Marie-Tooth disease type 4H	Benign (Feb 21, 2020)
12-32502163-A-C		Charcot-Marie-Tooth disease type 4H	Uncertain significance (Jan 13, 2018)
12-32502214-G-A		Charcot-Marie-Tooth disease type 4H	Uncertain significance (Jan 13, 2018)
12-32502295-A-G		Charcot-Marie-Tooth disease type 4H	Uncertain significance (Jan 13, 2018)
12-32502338-G-C		Charcot-Marie-Tooth disease type 4H	Benign (Jan 13, 2018)
12-32502347-C-T		Charcot-Marie-Tooth disease type 4H	Conflicting classifications of pathogenicity (Aug 07, 2020)
12-32534409-T-C			Uncertain significance (Jun 01, 2019)
12-32534418-A-G		not specified • FGD4-related disorder	Benign (-)
12-32563911-G-A			Benign (Mar 11, 2020)
12-32564014-GGGGAGA-G			Benign (Feb 04, 2021)
12-32564054-T-A			Benign (Mar 11, 2020)
12-32564077-T-C			Likely benign (Mar 11, 2020)
12-32564146-C-G		not specified	Likely benign (Jan 06, 2017)
12-32564238-A-T		Charcot-Marie-Tooth disease type 4H	Uncertain significance (Jan 13, 2018)
12-32564290-G-A		not specified	Uncertain significance (Dec 05, 2016)
12-32575927-A-G			Likely benign (Jun 16, 2018)
12-32576322-C-A		Charcot-Marie-Tooth disease type 4H • not specified	Conflicting classifications of pathogenicity (Jul 02, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FGD4	protein_coding	protein_coding	ENST00000427716	15	246522

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00982	0.990	125709	0	39	125748	0.000155

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.14	275	395	0.696	0.0000193	5064
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000145	0.000145
Ashkenazi Jewish	0.0000994	0.0000992
East Asian	0.000109	0.000109
Finnish	0.000139	0.000139
European (Non-Finnish)	0.000150	0.000149
Middle Eastern	0.000109	0.000109
South Asian	0.000327	0.000327
Other	0.000163	0.000163

dbNSFP

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.
• Pathway: Glucocorticoid Receptor Pathway;Nuclear Receptors Meta-Pathway;Signaling by GPCR;Signal Transduction;Rho GTPase cycle;Signaling by Rho GTPases;NRAGE signals death through JNK;Death Receptor Signalling;p75 NTR receptor-mediated signalling;G alpha (12/13) signalling events;GPCR downstream signalling;Cell death signalling via NRAGE, NRIF and NADE (Consensus)

Recessive Scores

• pRec: 0.130

Intolerance Scores

• loftool: 0.683
• rvis_EVS: -0.16
• rvis_percentile_EVS: 42.16

Haploinsufficiency Scores

• pHI: 0.111
• hipred: Y
• hipred_score: 0.524
• ghis: 0.458

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.0794

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fgd4
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: cytoskeleton organization;G protein-coupled receptor signaling pathway;regulation of cell shape;actin cytoskeleton organization;regulation of Rho protein signal transduction;positive regulation of apoptotic process;regulation of GTPase activity;filopodium assembly;regulation of small GTPase mediated signal transduction
• Cellular component: ruffle;cytoplasm;Golgi apparatus;cytosol;cytoskeleton;lamellipodium;filopodium
• Molecular function: actin binding;guanyl-nucleotide exchange factor activity;Rho guanyl-nucleotide exchange factor activity;small GTPase binding;metal ion binding