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SPAST

protein-coding

spastin, the group of AAA ATPases

Gene summary

This gene encodes a member of the AAA (ATPases associated with a variety of cellular activities) protein family. Members of this protein family share an ATPase domain and have roles in diverse cellular processes including membrane trafficking, intracellular motility, organelle biogenesis, protein folding, and proteolysis. The use of alternative translational initiation sites in this gene results in a single transcript variant that can produce isoforms that differ in the length of their N-terminus and which thereby differ in the efficiency of their export from the nucleus to the cytoplasm. In addition, alternative splicing results in multiple transcript variants that encode isoforms that differ in other protein regions as well. One isoform of this gene has been shown to be a microtubule-severing enzyme that regulates microtubule abundance, mobility, and plus-end distribution. Mutations in this gene cause the most frequent form of autosomal dominant spastic paraplegia 4. [provided by RefSeq, May 2018]

Previous symbols:
  • SPG4

MANE transcript

NM_014946.4

Inheritance

AD, AR

ClinVar variants

P:642U:369B:176

Top phenotype

Spastic paraplegia 4, autosomal dominant

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr2:32,063,556-32,157,637

External References & Databases

Ensembl (ENSG00000021574)NCBI Gene (6683)OMIM (604277)HGNC:11233GenCCUniProt (Q9UBP0)AlphaFoldClinVar (SPAST)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~94.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary spastic paraplegia 4SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008438

Submitter: Orphanet

hereditary spastic paraplegia 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008438

Submitter: PanelApp Australia

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

hereditary spastic paraplegia 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008438

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spastic paraplegia 4DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008438

Submitter: G2P

hereditary spastic paraplegia 4DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008438

Submitter: Illumina

hereditary spastic paraplegia 4MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0008438

Submitter: Ambry Genetics

SPAST-related motor disorderSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0100523

Submitter: Ambry Genetics

hereditary spastic paraplegia 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008438

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Spastic paraplegia 4, autosomal dominantAD

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: 9302257; 9736780; 10699187; 11134375; 11843700; 11309678; 12471215; 15159500; 15210521; 15248095; 14872021; 16682546; 16055926; 16832076; 17345589; 17098887; 17895902; 18401025; 19652142; 18701882; 19939411; 20301339; 20562464; 20932283; 21659953; 21834905; 22192498; 22960362Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SPAST variants in ClinVar

27 Conditions Cataloged
Hereditary spastic paraplegia 4Total: 1056
not providedTotal: 437
Inborn genetic diseasesTotal: 85
Hereditary spastic paraplegiaTotal: 76
not specifiedTotal: 44
SPAST-related disorderTotal: 26
Spastic paraplegiaTotal: 18
See casesTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014946.4. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
4
clinvar
8
clinvar
130
clinvar
 144
missense
77
clinvar
136
clinvar
352
clinvar
44
clinvar
 609
nonsense
74
clinvar
13
clinvar
1
clinvar
 88
start loss
1
clinvar
2
clinvar
 3
frameshift
183
clinvar
51
clinvar
2
clinvar
1
clinvar
 237
splice donor/acceptor (+/-2bp)
78
clinvar
23
clinvar
4
clinvar
1
clinvar
 106
Total41522736917511187

Highest pathogenic variant AF is 0.000008681104

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_014946.4RefSeqNP_055761.217MANE Select
ENST00000315285.9EnsemblENSP00000320885.317MANE Select
NM_001363823.2RefSeqNP_001350752.117Standard
NM_001363875.2RefSeqNP_001350804.116Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
spastDanio rerio

Structure: primary motor neuron

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • mitotic cytokinesis
  • microtubule bundle formation
  • endoplasmic reticulum to Golgi vesicle-mediated transport
  • axonogenesis
  • anterograde axonal transport

Molecular Function

  • protein binding
  • ATP binding
  • microtubule binding
  • microtubule-severing ATPase activity
  • isomerase activity

Cellular Component

  • ESCRT III complex
  • nucleus
  • nucleoplasm
  • cytoplasm
  • endosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000315285
Coding exons
17
Length
94027
Individuals with no LoFs
125740
Homozygous LoFs
0
Heterozygous LoFs
6
Defined
125746
p
0.0000239
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.242793440.8110.00001753967
Missense (PolyPhen)51121.740.418921478
Synonymous-2.361571241.270.000006021234
Loss of Function4.97334.60.08680.00000180410

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000120.00012rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.0000550.000054rare
Finnish00.0absent
European (Non-Finnish)0.0000260.000026rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated (PubMed:11809724, PubMed:15716377, PubMed:16219033, PubMed:17389232, PubMed:20530212, PubMed:22637577, PubMed:26875866). Preferentially recognizes and acts on microtubules decorated with short polyglutamate tails: severing activity increases as the number of glutamates per tubulin rises from one to eight, but decreases beyond this glutamylation threshold (PubMed:26875866). Severing activity is not dependent on tubulin acetylation or detyrosination (PubMed:26875866). Microtubule severing promotes reorganization of cellular microtubule arrays and the release of microtubules from the centrosome following nucleation. It is critical for the biogenesis and maintenance of complex microtubule arrays in axons, spindles and cilia. SPAST is involved in abscission step of cytokinesis and nuclear envelope reassembly during anaphase in cooperation with the ESCRT-III complex (PubMed:19000169, PubMed:21310966, PubMed:26040712). Recruited at the midbody, probably by IST1, and participates in membrane fission during abscission together with the ESCRT-III complex (PubMed:21310966). Recruited to the nuclear membrane by IST1 and mediates microtubule severing, promoting nuclear envelope sealing and mitotic spindle disassembly during late anaphase (PubMed:26040712). Required for membrane traffic from the endoplasmic reticulum (ER) to the Golgi and endosome recycling (PubMed:23897888). Recruited by IST1 to endosomes and regulates early endosomal tubulation and recycling by mediating microtubule severing (PubMed:23897888). Probably plays a role in axon growth and the formation of axonal branches (PubMed:15716377). {ECO:0000255|HAMAP-Rule:MF_03021, ECO:0000269|PubMed:11809724, ECO:0000269|PubMed:15716377, ECO:0000269|PubMed:16219033, ECO:0000269|PubMed:17389232, ECO:0000269|PubMed:19000169, ECO:0000269|PubMed:20530212, ECO:0000269|PubMed:21310966, ECO:0000269|PubMed:22637577, ECO:0000269|PubMed:23897888, ECO:0000269|PubMed:26040712, ECO:0000269|PubMed:26875866}.;
Disease
DISEASE: Spastic paraplegia 4, autosomal dominant (SPG4) [MIM:182601]: 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. {ECO:0000269|PubMed:10610178, ECO:0000269|PubMed:10699187, ECO:0000269|PubMed:11015453, ECO:0000269|PubMed:11039577, ECO:0000269|PubMed:11087788, ECO:0000269|PubMed:11309678, ECO:0000269|PubMed:11809724, ECO:0000269|PubMed:11843700, ECO:0000269|PubMed:11985387, ECO:0000269|PubMed:12124993, ECO:0000269|PubMed:12161613, ECO:0000269|PubMed:12163196, ECO:0000269|PubMed:12202986, ECO:0000269|PubMed:12460147, ECO:0000269|PubMed:12552568, ECO:0000269|PubMed:12939659, ECO:0000269|PubMed:14732620, ECO:0000269|PubMed:15159500, ECO:0000269|PubMed:15210521, ECO:0000269|PubMed:15248095, ECO:0000269|PubMed:15326248, ECO:0000269|PubMed:15482961, ECO:0000269|PubMed:15667412, ECO:0000269|PubMed:15716377, ECO:0000269|PubMed:15891913, ECO:0000269|PubMed:16339213, ECO:0000269|PubMed:16682546, ECO:0000269|PubMed:16684598, ECO:0000269|PubMed:17389232, ECO:0000269|PubMed:17594340, ECO:0000269|PubMed:19000169, ECO:0000269|PubMed:20214791, ECO:0000269|PubMed:20550563, ECO:0000269|PubMed:20562464, ECO:0000269|PubMed:20718791, ECO:0000269|PubMed:20932283, ECO:0000269|PubMed:21546041, ECO:0000269|PubMed:22960362, ECO:0000269|PubMed:23279441, ECO:0000269|PubMed:24824479, ECO:0000269|PubMed:25045380, ECO:0000269|PubMed:25421405, ECO:0000269|PubMed:28572275}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.198

Intolerance Scores

LoFtool
0.0336
RVIS EVS
-0.07
RVIS percentile EVS
48.54

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.508

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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