SPAST
  • 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
SPAST (HGNC:11233) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
spastin
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
SPG4
Alias symbols
FSP2, ADPSP, KIAA1083
%HI
9.51(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.11(Read more about gnomAD pLI score)
LOEUF
0.69(Read more about gnomAD LOEUF score)
Cytoband
2p22.3
Genomic Coordinates
GRCh37/hg19: chr2:32288625-32382706 NCBI Ensembl UCSC
GRCh38/hg38: chr2:32063556-32157637 NCBI Ensembl UCSC
MANE Select Transcript
NM_014946.4 ENST00000315285.9 (Read more about MANE Select)
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). Seve... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-16468
ClinGen Curation ID:
CCID:007927
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Read full report...
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Read full report...
Last Evaluated:
09/25/2019

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • Autosomal dominant Spastic Paraplegia 4 Monarch
HI Evidence:
  • PUBMED: 24690193
    Racis et al. (2014) described a family with spastic paralplegia 4 (SPG4) . Five of 25 family members were found to have a 51 kb deletion (5'UTR -exon 4). Four of the five carriers were had symptoms of SPG4 including walking abnormalities and stiffness. One of the carriers was asymptomatic. Authors highlighted that it was unclear if the asymptomatic carrier would manifest features of SPG4 in the future or will remain asymptomatic. Authors also looked at mRNA expression in three carriers (including the symptomatic carrier) . All three showed reduced mRNA levels of the SPAST and DPY30 when compared to controls. The DPY30 gene is a located upstream to the SPAST gene. Authors suggest that surrounding genes may be candidates for modulating clinical phenotype and explain the variability seen in SPG4.
  • PUBMED: 28572275
    Chelban et al. (2017) investigated 118 patients from 104 families from the UK referred as SPAST positive and with hereditary spastic paraplegia (HSP). The authors assessed phenotypic and genotypic spectrum of SPAST related HSP. The frequency of the variants were highlighted including 61% loss of function (LoF) variants (11% whole exon deletions, 22% frameshift, 1% partial gene duplications, 7% nonsense, 17% splicing and 3% in frame deletions). Authors data also highlighted that a subset of patients also showed features of psychiatric disorders and autism
  • PUBMED: 15667412
    Nielsen et al. (2004) described a 4- generation Danish family with autosomal dominant HSP and additional phenotypes within the family including ataxia, dysarthria, unipolar depression, epilepsy, migraine and cognitive impairment . Sequence analysis identified a 1593 c>T (GLN490Stop) variant which leads to a premature termination codon in exon 12. This variant co-segregated with HSP and ataxia. Authors note that epilepsy, dysarthria, unipolar depression, migraine and cognitive impairment did not segregate with the HSP phenotype.
HI Evidence Comments:
Heterozygous LoF sequence variants, as well as partial or entire deletions of SPAST cause autosomal dominant spastic paraplegia-4 (SPG4). Pathogenic sequence variants in SPAST gene are more frequent in familial than in sporadic cases. Large deletions have been found only in familial patients. Additional publications: PMIDs: 29980238; 25065914; 28572275; 27334366 Further, two de novo frameshift variants are reported in two patients with autism spectrum disorder (PMIDs 25363768 and PMID 22495311). However, haploinsufficiency of SPAST has not yet been established in autism.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)
TS Evidence Comments:
At this time there have been no reports of whole duplications of the SPAST gene associated with a phenotype.

Genomic View

Select assembly: (NC_000002.11) (NC_000002.12)