SPG7

SPG7 matrix AAA peptidase subunit, paraplegin, the group of AAA ATPases

Basic information

Region (hg38): 16:89490719-89557766

Previous symbols: [ "CMAR" ]

Links

ENSG00000197912 ∙ NCBI:6687 ∙ OMIM:602783 ∙ HGNC:11237 ∙ Uniprot:Q9UQ90 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• hereditary spastic paraplegia 7 (Definitive), mode of inheritance: AR
• lateral sclerosis (Supportive), mode of inheritance: AD
• hereditary spastic paraplegia 7 (Supportive), mode of inheritance: AD
• hereditary spastic paraplegia 7 (Strong), mode of inheritance: AR
• hereditary spastic paraplegia 7 (Definitive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Spastic paraplegia 7, 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	9635427; 9634528; 16534102; 18200586; 18799786; 20108356; 21623769; 22571692; 22964162
Heterozygotes may demonstrate manifestations

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SPG7 gene.

• Hereditary_spastic_paraplegia_7 (772 variants)
• not_provided (392 variants)
• Inborn_genetic_diseases (108 variants)
• not_specified (106 variants)
• Hereditary_spastic_paraplegia (69 variants)
• SPG7-related_disorder (41 variants)
• Retinal_dystrophy (10 variants)
• Spastic_ataxia (5 variants)
• Leukoencephalopathy_with_vanishing_white_matter_1 (4 variants)
• Hereditary_ataxia (3 variants)
• Spastic_paraplegia (2 variants)
• Spastic_paraparesis (2 variants)
• Intellectual_disability (2 variants)
• Spastic_Paraplegia,_Recessive (2 variants)
• Mitochondrial_disease (2 variants)
• Sensorimotor_neuropathy (2 variants)
• Optic_atrophy (2 variants)
• Cerebral_cortical_atrophy (2 variants)
• Dysarthria (2 variants)
• Gait_ataxia (2 variants)
• Hereditary_pancreatitis (1 variants)
• Optic_nerve_hypoplasia (1 variants)
• Polyneuropathy (1 variants)
• Proximal_spinal_muscular_atrophy (1 variants)
• Frontotemporal_dementia_and/or_amyotrophic_lateral_sclerosis_2 (1 variants)
• Seizure (1 variants)
• Memory_impairment (1 variants)
• Spastic_tetraparesis (1 variants)
• Distal_spinal_muscular_atrophy (1 variants)
• Early-onset_progressive_neurodegeneration-blindness-ataxia-spasticity_syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SPG7 gene is commonly pathogenic or not. These statistics are base on transcript: NM_000003119.4. 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	1		16	166	5	188
missense	9	48	414	17	2	490
nonsense	15	23	4			42
start loss	1	6				7
frameshift	37	32	3			72
splice donor/acceptor (+/-2bp)	10	18				28
Total	73	127	437	183	7

Highest pathogenic variant AF is 0.0057954653

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SPG7	protein_coding	protein_coding	ENST00000268704	17	66852

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.97e-36	8.36e-8	125322	2	424	125748	0.00170

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.872	528	475	1.11	0.0000342	5129
Missense in Polyphen		205	215.61	0.95079		2137
Synonymous	-4.22	279	203	1.38	0.0000163	1632
Loss of Function	-1.69	48	36.9	1.30	0.00000225	416

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00212	0.00212
Ashkenazi Jewish	0.000497	0.000496
East Asian	0.000979	0.000979
Finnish	0.00107	0.00106
European (Non-Finnish)	0.00195	0.00191
Middle Eastern	0.000979	0.000979
South Asian	0.00357	0.00350
Other	0.00164	0.00163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: ATP-dependent zinc metalloprotease. Plays a role in the formation and regulation of the mitochondrial permeability transition pore (mPTP) and its proteolytic activity is dispensable for this function (PubMed:26387735). {ECO:0000269|PubMed:26387735, ECO:0000305}.
• Disease: DISEASE: Spastic paraplegia 7, autosomal recessive (SPG7) [MIM:607259]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG7 is a complex form. Additional clinical features are cerebellar syndrome, supranuclear palsy, and cognitive impairment, particularly disturbance of attention and executive functions. {ECO:0000269|PubMed:16534102, ECO:0000269|PubMed:17646629, ECO:0000269|PubMed:20186691, ECO:0000269|PubMed:27217339, ECO:0000269|PubMed:9635427}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in SPG7 may cause autosomal recessive osteogenesis imperfecta (OI). Osteogenesis imperfecta defines a group of connective tissue disorders characterized by bone fragility and low bone mass. Clinical features of SPG7-related osteogenesis imperfecta include recurrent fractures, mild bone deformities, delayed tooth eruption, normal hearing and white sclera. {ECO:0000269|PubMed:20579626}.
• Pathway: Transport of small molecules;Mitochondrial calcium ion transport;Processing of SMDT1 (Consensus)

Intolerance Scores

• loftool: 0.103
• rvis_EVS: -1.05
• rvis_percentile_EVS: 7.62

Haploinsufficiency Scores

• pHI: 0.140
• hipred: N
• hipred_score: 0.294
• ghis: 0.624

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.975

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Spg7
• Phenotype: growth/size/body region phenotype; skeleton phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); 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)

Gene ontology

• Biological process: proteolysis;mitochondrial calcium ion transmembrane transport;mitochondrion organization;nervous system development;anterograde axonal transport;regulation of mitochondrial membrane permeability;mitochondrial outer membrane permeabilization involved in programmed cell death
• Cellular component: mitochondrion;mitochondrial inner membrane;m-AAA complex;mitochondrial permeability transition pore complex;axon cytoplasm
• Molecular function: metalloendopeptidase activity;protein binding;ATP binding;peptidase activity;zinc ion binding;unfolded protein binding