SPG11

SPG11 vesicle trafficking associated, spatacsin

Basic information

Region (hg38): 15:44554818-44663688

Previous symbols: [ "KIAA1840", "ALS5" ]

Links

ENSG00000104133 ∙ NCBI:80208 ∙ OMIM:610844 ∙ HGNC:11226 ∙ Uniprot:Q96JI7 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary spastic paraplegia 11 (Definitive), mode of inheritance: AR
• hereditary spastic paraplegia 11 (Strong), mode of inheritance: AR
• Charcot-Marie-Tooth disease axonal type 2X (Strong), mode of inheritance: AR
• amyotrophic lateral sclerosis type 5 (Strong), mode of inheritance: AR
• hereditary spastic paraplegia 11 (Definitive), mode of inheritance: AR
• hereditary spastic paraplegia 11 (Supportive), mode of inheritance: AR
• juvenile amyotrophic lateral sclerosis (Supportive), mode of inheritance: AR
• Charcot-Marie-Tooth disease axonal type 2X (Supportive), mode of inheritance: AR
• amyotrophic lateral sclerosis type 5 (Strong), mode of inheritance: AR
• Charcot-Marie-Tooth disease axonal type 2X (Strong), mode of inheritance: AR
• hereditary spastic paraplegia 11 (Strong), mode of inheritance: AR
• hereditary spastic paraplegia 11 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Amyotrophic lateral sclerosis 5, juvenile recessive; Charcot-Marie-Tooth disease, axonal, type 2X; Spastic paraplegia 11, autosomal recessive	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	17717710; 18067136; 17322883; 18663179; 18787847; 19196735; 19194956; 19513778; 20108361; 20110243; 20301389; 20390432; 20571989; 20971220; 21035867; 21381113; 21625935; 22154821; 22175763; 23043354; 23121729; 26556829

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SPG11 gene.

• Hereditary_spastic_paraplegia_11 (3077 variants)
• not_provided (601 variants)
• Inborn_genetic_diseases (571 variants)
• Amyotrophic_lateral_sclerosis_type_5 (315 variants)
• Charcot-Marie-Tooth_disease_axonal_type_2X (313 variants)
• Hereditary_spastic_paraplegia (150 variants)
• not_specified (105 variants)
• SPG11-related_disorder (58 variants)
• Amyotrophic_lateral_sclerosis (10 variants)
• Juvenile_amyotrophic_lateral_sclerosis (5 variants)
• Abnormal_central_motor_function (5 variants)
• Spastic_Paraplegia,_Recessive (4 variants)
• See_cases (4 variants)
• Intellectual_disability (3 variants)
• Spastic_paraplegia (2 variants)
• Spastic_paraparesis (2 variants)
• Metabolic_disease (2 variants)
• SPG11-related_spastic_paraplegia (2 variants)
• Gait_disturbance (2 variants)
• Neurofibromatosis,_type_1 (2 variants)
• Difficulty_walking (2 variants)
• Generalized_hyperreflexia (2 variants)
• Autism_spectrum_disorder (1 variants)
• Early-onset_Parkinson_disease_20 (1 variants)
• Charcot-Marie-Tooth_disease (1 variants)
• Abnormal_brain_morphology (1 variants)
• Cerebral_amyloid_angiopathy,_APP-related (1 variants)
• Spastic_ataxia (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SPG11 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000025137.4. 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		2	26	820	5	853
missense	7	10	1318	63	7	1405
nonsense	110	42	12			164
start loss			1			1
frameshift	217	75	27			319
splice donor/acceptor (+/-2bp)	21	60	1			82
Total	355	189	1385	883	12

Highest pathogenic variant AF is 0.00017781225

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SPG11	protein_coding	protein_coding	ENST00000261866	40	100983

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.60e-39	0.947	125367	0	381	125748	0.00152

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-1.39	1360	1.22e+3	1.11	0.0000609	16162
Missense in Polyphen		429	412.9	1.039		5520
Synonymous	-2.17	521	462	1.13	0.0000228	4514
Loss of Function	3.30	81	120	0.675	0.00000584	1505

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00264	0.00258
Ashkenazi Jewish	0.000993	0.000993
East Asian	0.00158	0.00158
Finnish	0.000647	0.000647
European (Non-Finnish)	0.00186	0.00186
Middle Eastern	0.00158	0.00158
South Asian	0.00151	0.00150
Other	0.00114	0.00114

dbNSFP

Source: dbNSFP

• Function: FUNCTION: May play a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport. {ECO:0000269|PubMed:24794856}.
• Disease: DISEASE: Amyotrophic lateral sclerosis 5, juvenile (ALS5) [MIM:602099]: A form of amyotrophic lateral sclerosis, 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. ALS5 is an autosomal recessive, juvenile form characterized by onset of upper and lower motor neuron signs before age 25. {ECO:0000269|PubMed:20110243}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 2X (CMT2X) [MIM:616668]: An autosomal recessive, axonal 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). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. CMT2X patients manifest a slowly progressive, peripheral neuropathy affecting the lower limbs and resulting in gait difficulties and distal sensory impairment. Some patients also have upper limb involvement. {ECO:0000269|PubMed:26556829}. Note=The disease is caused by mutations affecting the gene represented in this entry.

Recessive Scores

• pRec: 0.113

Intolerance Scores

• loftool: 0.615
• rvis_EVS: -0.48
• rvis_percentile_EVS: 22.79

Haploinsufficiency Scores

• pHI: 0.483
• hipred: N
• hipred_score: 0.414
• ghis: 0.542

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.414

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Spg11
• 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); cellular phenotype; growth/size/body region phenotype

Zebrafish Information Network

• Gene name: spg11
• Affected structure: retinal ganglion cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: chemical synaptic transmission;axo-dendritic transport;synaptic vesicle transport;axon extension;phagosome-lysosome fusion involved in apoptotic cell clearance;walking behavior
• Cellular component: nucleolus;cytoplasm;lysosomal membrane;cytosol;plasma membrane;axon;dendrite;cytoplasmic vesicle;synapse
• Molecular function: protein binding