FIG4

FIG4 phosphoinositide 5-phosphatase, the group of Phosphoinositide phosphatases

Basic information

Region (hg38): 6:109690609-109878098

Previous symbols: [ "KIAA0274" ]

Links

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

Phenotypes

GenCC

Source: genCC

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

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Amyotrophic lateral sclerosis 11; Charcot-Marie Tooth disease, demyelinating, 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 (828 variants)
• not_provided (224 variants)
• Inborn_genetic_diseases (215 variants)
• Charcot-Marie-Tooth_disease_type_4J (94 variants)
• Charcot-Marie-Tooth_disease (83 variants)
• FIG4-related_disorder (76 variants)
• Amyotrophic_lateral_sclerosis_type_11 (70 variants)
• not_specified (57 variants)
• Yunis-Varon_syndrome (44 variants)
• Bilateral_parasagittal_parieto-occipital_polymicrogyria (25 variants)
• Amyotrophic_lateral_sclerosis (14 variants)
• See_cases (3 variants)
• Cerebral_hypomyelination (2 variants)
• Neuronopathy,_distal_hereditary_motor,_autosomal_dominant (1 variants)
• Penile_hypospadias (1 variants)
• Severe_global_developmental_delay (1 variants)
• Leukemia,_chronic_lymphocytic,_susceptibility_to,_3 (1 variants)
• Charcot-Marie-Tooth_disease,_type_I (1 variants)
• Micropenis (1 variants)
• Failure_to_thrive (1 variants)
• Abnormality_of_the_skeletal_system (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. These statistics are base on transcript: NM_000014845.6. Only rare variants are included in the table.

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.

Effect	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			9	204	1	214
missense	1	11	400	12		424
nonsense	26	12	4			42
start loss	3					3
frameshift	34	12	4			50
splice donor/acceptor (+/-2bp)	3	30	7		1	41
Total	67	65	424	216	2

Highest pathogenic variant AF is 0.0015361633

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
		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

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

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