FIG4

FIG4 phosphoinositide 5-phosphatase, the group of Phosphoinositide phosphatases

Basic information

Region (hg38): 6:109690608-109878098

Previous symbols: [ "KIAA0274" ]

Links

ENSG00000112367 ∙ NCBI:9896 ∙ OMIM:609390 ∙ HGNC:16873 ∙ Uniprot:Q92562 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Yunis-Varon syndrome (Strong), mode of inheritance: AR
• amyotrophic lateral sclerosis type 11 (Strong), mode of inheritance: AD
• Charcot-Marie-Tooth disease type 4J (Definitive), mode of inheritance: AR
• amyotrophic lateral sclerosis (Supportive), mode of inheritance: AD
• Yunis-Varon syndrome (Supportive), mode of inheritance: AR
• Charcot-Marie-Tooth disease type 4J (Supportive), mode of inheritance: AR
• bilateral parasagittal parieto-occipital polymicrogyria (Supportive), mode of inheritance: AR
• Charcot-Marie-Tooth disease type 4J (Definitive), mode of inheritance: AR
• Charcot-Marie-Tooth disease (Definitive), mode of inheritance: AR
• amyotrophic lateral sclerosis type 11 (Limited), mode of inheritance: Unknown
• Charcot-Marie-Tooth disease type 4J (Strong), mode of inheritance: AR
• Yunis-Varon syndrome (Strong), mode of inheritance: AR
• Charcot-Marie-Tooth disease (Definitive), mode of inheritance: AR
• amyotrophic lateral sclerosis type 11 (Limited), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Amyotrophic lateral sclerosis 11; Charcot-Marie Tooth disease, autosomal recessive, type 4J; Polymicrogyria, bilateral temporooccipital; Yunis-Varon syndrome	AD/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	Craniofacial; Musculoskeletal; Neurologic	17572665; 18758830; 19118816; 21705420; 23623387; 24598713; 24878229

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FIG4 gene.

• Charcot-Marie-Tooth disease type 4 (689 variants)
• not provided (227 variants)
• Inborn genetic diseases (149 variants)
• Charcot-Marie-Tooth disease type 4J (92 variants)
• Charcot-Marie-Tooth disease (88 variants)
• Amyotrophic lateral sclerosis type 11 (74 variants)
• not specified (54 variants)
• Yunis-Varon syndrome (24 variants)
• FIG4-related condition (15 variants)
• Bilateral parasagittal parieto-occipital polymicrogyria (15 variants)
• Amyotrophic lateral sclerosis (7 variants)
• FIG4-Related Disorders (6 variants)
• Amyotrophic lateral sclerosis type 11;Charcot-Marie-Tooth disease type 4J;Yunis-Varon syndrome;Bilateral parasagittal parieto-occipital polymicrogyria (4 variants)
• Amyotrophic lateral sclerosis type 11;Charcot-Marie-Tooth disease type 4J (3 variants)
• Cerebral hypomyelination (2 variants)
• See cases (2 variants)
• Bilateral parasagittal parieto-occipital polymicrogyria;Amyotrophic lateral sclerosis type 11;Charcot-Marie-Tooth disease type 4J;Yunis-Varon syndrome (2 variants)
• Yunis-Varon syndrome;Charcot-Marie-Tooth disease type 4J (2 variants)
• Amyotrophic Lateral Sclerosis, Dominant (1 variants)
• Amyotrophic lateral sclerosis type 11;Bilateral parasagittal parieto-occipital polymicrogyria;Charcot-Marie-Tooth disease type 4J;Yunis-Varon syndrome (1 variants)
• Tremor (1 variants)
• Yunis-Varon syndrome;Bilateral parasagittal parieto-occipital polymicrogyria;Amyotrophic lateral sclerosis type 11;Charcot-Marie-Tooth disease type 4J (1 variants)
• Failure to thrive;Abnormality of the skeletal system;Penile hypospadias;Micropenis;Severe global developmental delay (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FIG4 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			7	136	1	144
missense		2	334	3	1	340
nonsense	17	8	3			28
start loss	2					2
frameshift	29	6	1			36
inframe indel			4			4
splice donor/acceptor (+/-2bp)	2	23	1	1	2	29
splice region			33	32	4	69
non coding			17	125	56	198
Total	50	39	367	265	60

Highest pathogenic variant AF is 0.000217

Variants in FIG4

This is a list of pathogenic ClinVar variants found in the FIG4 region.

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

Position	Type	Phenotype	Significance	ClinVar
6-109691071-A-G			Likely benign (Jun 20, 2018)
6-109691254-G-A		Amyotrophic lateral sclerosis type 11 • Charcot-Marie-Tooth disease type 4J	Benign/Likely benign (Jun 14, 2018)
6-109691284-C-A		Charcot-Marie-Tooth disease type 4J • Amyotrophic lateral sclerosis type 11	Uncertain significance (Jan 13, 2018)
6-109691298-T-C		Amyotrophic lateral sclerosis type 11 • Charcot-Marie-Tooth disease type 4J	Uncertain significance (Jan 13, 2018)
6-109691302-C-G		Amyotrophic lateral sclerosis type 11 • Charcot-Marie-Tooth disease type 4J	Uncertain significance (Jan 13, 2018)
6-109691304-A-G		Charcot-Marie-Tooth disease type 4J • Amyotrophic lateral sclerosis type 11	Uncertain significance (Jan 13, 2018)
6-109691312-A-G		Charcot-Marie-Tooth disease type 4J • Amyotrophic lateral sclerosis type 11	Uncertain significance (Jan 13, 2018)
6-109691315-G-A		Amyotrophic lateral sclerosis type 11 • Charcot-Marie-Tooth disease type 4J	Benign (Jan 06, 2019)
6-109691316-C-T		Charcot-Marie-Tooth disease type 4J • Amyotrophic lateral sclerosis type 11	Benign (Nov 25, 2019)
6-109691324-G-A		Charcot-Marie-Tooth disease type 4J • Amyotrophic lateral sclerosis type 11	Uncertain significance (Jan 12, 2018)
6-109691352-A-G		Charcot-Marie-Tooth disease type 4J • Amyotrophic lateral sclerosis type 11	Uncertain significance (Jan 13, 2018)
6-109691426-TGCCGCCGCCATGCCCACG-T		Charcot-Marie-Tooth disease type 4	Pathogenic (Jul 24, 2021)
6-109691433-G-GCCATGCCCACGGCCGCCGCCC		Charcot-Marie-Tooth disease type 4	Uncertain significance (May 03, 2018)
6-109691436-A-C		Charcot-Marie-Tooth disease type 4	Pathogenic (Jul 27, 2021)
6-109691436-A-G		Charcot-Marie-Tooth disease type 4	Pathogenic (Jan 13, 2023)
6-109691442-A-T		Charcot-Marie-Tooth disease type 4	Uncertain significance (Dec 07, 2023)
6-109691449-C-T		Charcot-Marie-Tooth disease type 4 • Inborn genetic diseases	Uncertain significance (Nov 01, 2022)
6-109691450-C-T		Charcot-Marie-Tooth disease type 4	Likely benign (Jun 03, 2023)
6-109691451-G-T		Charcot-Marie-Tooth disease type 4	Uncertain significance (Apr 01, 2024)
6-109691451-GC-G		Charcot-Marie-Tooth disease type 4	Pathogenic (Sep 07, 2022)
6-109691453-C-G		Charcot-Marie-Tooth disease type 4	Likely benign (Feb 19, 2022)
6-109691454-C-T		Charcot-Marie-Tooth disease type 4	Uncertain significance (Sep 24, 2021)
6-109691462-C-T		not specified • Charcot-Marie-Tooth disease type 4 • Amyotrophic lateral sclerosis type 11 • Charcot-Marie-Tooth disease • Charcot-Marie-Tooth disease type 4J • Amyotrophic lateral sclerosis type 11;Bilateral parasagittal parieto-occipital polymicrogyria;Charcot-Marie-Tooth disease type 4J;Yunis-Varon syndrome • Inborn genetic diseases • FIG4-related disorder	Benign/Likely benign (Apr 01, 2024)
6-109691464-G-A		Charcot-Marie-Tooth disease type 4	Uncertain significance (Jun 04, 2022)
6-109691468-G-C		not specified • Charcot-Marie-Tooth disease type 4J • Amyotrophic lateral sclerosis type 11 • Charcot-Marie-Tooth disease • Charcot-Marie-Tooth disease type 4 • Inborn genetic diseases • FIG4-related disorder	Conflicting classifications of pathogenicity (Aug 22, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FIG4	protein_coding	protein_coding	ENST00000230124	23	134133

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
2.34e-34	0.0000193	125552	0	196	125748	0.000780

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.88	381	499	0.764	0.0000267	5964
Missense in Polyphen		88	135.61	0.64893		1632
Synonymous	-0.464	182	174	1.04	0.00000899	1683
Loss of Function	0.104	52	52.8	0.985	0.00000282	635

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00185	0.00185
Ashkenazi Jewish	0.00	0.00
East Asian	0.00131	0.00131
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.000855	0.000835
Middle Eastern	0.00131	0.00131
South Asian	0.000787	0.000784
Other	0.000491	0.000489

dbNSFP

Source: dbNSFP

• Function: FUNCTION: The PI(3,5)P2 regulatory complex regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2). In vitro, hydrolyzes all three D5-phosphorylated polyphosphoinositide substrates in the order PtdIns(4,5)P2 > PtdIns(3,5)P2 > PtdIns(3,4,5)P3. Plays a role in the biogenesis of endosome carrier vesicles (ECV) / multivesicular bodies (MVB) transport intermediates from early endosomes. {ECO:0000269|PubMed:17556371}.
• Disease: DISEASE: Charcot-Marie-Tooth disease 4J (CMT4J) [MIM:611228]: 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:17572665, ECO:0000269|PubMed:21655088, ECO:0000269|PubMed:21705420}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Amyotrophic lateral sclerosis 11 (ALS11) [MIM:612577]: A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5- 10% of the cases. {ECO:0000269|PubMed:19118816}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Yunis-Varon syndrome (YVS) [MIM:216340]: A severe autosomal recessive disorder characterized by skeletal defects, including cleidocranial dysplasia and digital anomalies, and severe neurologic involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found in neurons, muscle, and cartilage. The disorder is usually lethal in infancy. {ECO:0000269|PubMed:23623387}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Polymicrogyria, bilateral temporooccipital (BTOP) [MIM:612691]: A disease characterized by temporo-occipital polymicrogyria, psychiatric manifestations, and epilepsy. {ECO:0000269|PubMed:24598713}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Phosphatidylinositol Phosphate Metabolism;Joubert syndrome;Inositol Metabolism;Metabolism of lipids;Metabolism;3-phosphoinositide biosynthesis;superpathway of inositol phosphate compounds;Synthesis of PIPs at the Golgi membrane;Synthesis of PIPs at the early endosome membrane;Synthesis of PIPs at the late endosome membrane;PI Metabolism;Phospholipid metabolism (Consensus)

Recessive Scores

• pRec: 0.132

Intolerance Scores

• loftool: 0.977
• rvis_EVS: -0.31
• rvis_percentile_EVS: 32.17

Haploinsufficiency Scores

• pHI: 0.106
• hipred: N
• hipred_score: 0.393
• ghis: 0.505

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.729

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Fig4
• 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); skeleton phenotype; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); pigmentation phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); growth/size/body region phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); craniofacial phenotype; muscle phenotype

Gene ontology

• Biological process: phosphatidylinositol biosynthetic process;vacuole organization;locomotory behavior;positive regulation of neuron projection development;dephosphorylation;negative regulation of myelination;myelin assembly;phosphatidylinositol-3-phosphate biosynthetic process;pigmentation;neuron development
• Cellular component: Golgi membrane;endoplasmic reticulum;lipid droplet;endosome membrane;early endosome membrane;late endosome membrane;intracellular membrane-bounded organelle;recycling endosome
• Molecular function: phosphatidylinositol-3-phosphatase activity;protein binding;phosphatidylinositol-4-phosphate phosphatase activity;phosphatidylinositol-3,5-bisphosphate 5-phosphatase activity