SBF1

protein-coding

SET binding factor 1, the group of Myotubularins|Pleckstrin homology domain containing|DENN domain containing

Gene summary

This gene encodes a member of the protein-tyrosine phosphatase family. However, the encoded protein does not appear to be a catalytically active phosphatase because it lacks several amino acids in the catalytic pocket. This protein contains a Guanine nucleotide exchange factor (GEF) domain which is necessary for its role in growth and differentiation. Mutations in this gene have been associated with Charcot-Marie-Tooth disease 4B3. Pseudogenes of this gene have been defined on chromosomes 1 and 8. [provided by RefSeq, Dec 2014]

MANE transcript

NM_002972.4

Inheritance

ClinVar variants

P:61U:815B:662

Top phenotype

Charcot-Marie-Tooth disease, type 4B3

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr22:50,443,219-50,483,923

External References & Databases

Ensembl (ENSG00000100241)

Transcript & Mutation Effects

hg38 • Region Span ~40.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease type 4B3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014117

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease type 4B3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014117

Submitter: Labcorp Genetics (formerly Invitae)

Charcot-Marie-Tooth disease type 4B3LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014117

Submitter: Ambry Genetics

Charcot-Marie-Tooth disease type 4B3MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014117

Submitter: ClinGen

The gene SBF1 (set-binding factor 1), located at position 22q13.33, encodes a myotubularin-related protein (MTMR5) that is responsible for the subcellular localization of MTMR2, which is likewise CMT-associated. Structurally, it resembles SBF2/MTMR13. Together, all three MTMR proteins have been associated with autosomal recessive, demyelinating CMT with myelin outfoldings (CMT4). With the according phenotype, SBF1 was first identified by whole-exome-sequencing in three affected Korean individuals, who carried two missense variants in compound-heterozygosity (PMID: 23749797). Since then, however, no further family has been described carrying SBF1 mutations in association with CMT4B3. In contrast, five families (PMIDs: 24799518, 28005197, 32444983, 20658556, 30039846) of Saudi Arabian, Syrian, Isrealian, Spanish, and British descent have been identified with an axonal motor predominant neuropathy and cranial nerve involvement, including facial and ophthalmoparesis. As an imaging correlate, some of these patients showed T2-hyperintensities in pons and mesencephalon, called “fork and bracket” sign. Additional features repeatedly found in these families were spasticity, syndactyly, short stature, and intellectual disability. All affected individuals carried homozygous or compound-heterozygous variants in SBF1, including missense, splice, and frameshift mutations. We additionally reported another, yet unpublished case from US American Origin, matching this genotype-phenotype pattern. SBF1 is expressed in sural nerves (PMID: 23749797). Its interaction with MTMR2 has been shown by co-immunoprecipitation and confocal microscopy (PMID: 12668758). Unlike SBF2, SBF1-/- mice do not reproduce the clinical CMT phenotype (PMID: 11994405), but shown by electron microscopy, they seem to have a disturbed sorting of peripheral axon bundles (Mammel et al., 2019, evidence not scored). In summary, our score system suggests to classify the gene-disease relationship between SBF1 and autosomal recessive axonal neuropathy with cranial nerve involvement as MODERATE. This is mostly supported by genetic/clinical evidence and has been upheld over time, however, functional data on the underlying pathophysiology is lacking. The identification of more cases will most likely shift this classification towards “definitive” in the future. Evidence is insufficient to support or refute an association with demyelinating CMT4B. **Recuration Update**: No new literature evidence was found in 2026 so the classification remains unmodified.

Charcot-Marie-Tooth disease type 4B3SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014117

Submitter: Orphanet

Clinical Genomic Database (CGD)

Charcot-Marie-Tooth disease, type 4B3AR

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: 21210780; 23749797; 24799518

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SBF1 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 1875

not specifiedTotal: 548

Charcot-Marie-Tooth disease type 4B3Total: 129

SBF1-related disorderTotal: 80

Tip-toe gaitTotal: 64

Peripheral neuropathyTotal: 2

MicrocephalyTotal: 2

Charcot-Marie-Tooth diseaseTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002972.4. 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	1 clinvar		11 clinvar	601 clinvar	12 clinvar	625
missense		21 clinvar	791 clinvar	38 clinvar	11 clinvar	861
nonsense	8 clinvar	5 clinvar	2 clinvar			15
start loss						0
frameshift	10 clinvar	6 clinvar	4 clinvar			20
splice donor/acceptor (+/-2bp)		10 clinvar	7 clinvar			17
Total	19	42	815	639	23	1538

Highest pathogenic variant AF is 0.00024659414

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 90 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002972.4	RefSeq	NP_002963.2	41	MANE Select
ENST00000380817.8	Ensembl	ENSP00000370196.2	41	MANE Select
NM_001365819.1	RefSeq	NP_001352748.1	40	Standard
NM_001410794.1	RefSeq	NP_001397723.1	41	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Metabolism of lipids
Metabolism
Synthesis of PIPs at the ER membrane

Biological Process

protein dephosphorylation
phosphatidylinositol biosynthetic process
spermatogenesis
regulation of GTPase activity

Molecular Function

protein tyrosine/serine/threonine phosphatase activity
phosphatase activity
Rab guanyl-nucleotide exchange factor activity
phosphatase regulator activity

Cellular Component

cytoplasm
endoplasmic reticulum membrane
cytosol
integral component of membrane
nuclear body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000380817
Coding exons: 41
Length: 30026
Individuals with no LoFs: 124863
Homozygous LoFs: 0
Heterozygous LoFs: 29
Defined: 124892
p: 0.000116

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.527	1179	1.23e+3	0.958	0.0000893	12063
Missense (PolyPhen)		422	528.32	0.79876		5142
Synonymous	-7.01	740	534	1.39	0.0000391	3934
Loss of Function	7.32	16	91.6	0.175	0.00000451	1002

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00017	0.00017	rare
Finnish	0.000094	0.000093	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.000066	0.000065	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probable pseudophosphatase. Lacks several amino acids in the catalytic pocket which renders it catalytically inactive as a phosphatase. The pocket is however sufficiently preserved to bind phosphorylated substrates, and maybe protect them from phosphatases. Inhibits myoblast differentiation in vitro and induces oncogenic transformation in fibroblasts. According to PubMed:20937701, may function as a guanine nucleotide exchange factor (GEF) activating RAB28. Promotes the exchange of GDP to GTP, converting inactive GDP-bound Rab proteins into their active GTP-bound form. {ECO:0000269|PubMed:20937701, ECO:0000269|PubMed:9537414}.;
Disease: DISEASE: Charcot-Marie-Tooth disease 4B3 (CMT4B3) [MIM:615284]: 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:23749797}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.145

Intolerance Scores

LoFtool: 0.0648
RVIS EVS: -4.05
RVIS percentile EVS: 0.17

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.323

Gene Damage Prediction

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