chr2-32137157-A-T
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong
The NM_014946.4(SPAST):c.1462A>T(p.Arg488Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R488G) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
SPAST
NM_014946.4 missense
NM_014946.4 missense
Scores
13
4
1
Clinical Significance
Conservation
PhyloP100: 5.18
Genes affected
SPAST (HGNC:11233): (spastin) 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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM1
In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_014946.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-32137157-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 989179.Status of the report is criteria_provided_single_submitter, 1 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.942
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SPAST | NM_014946.4 | c.1462A>T | p.Arg488Trp | missense_variant | 12/17 | ENST00000315285.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SPAST | ENST00000315285.9 | c.1462A>T | p.Arg488Trp | missense_variant | 12/17 | 1 | NM_014946.4 | P4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia 4 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 21, 2017 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with SPAST-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with tryptophan at codon 488 of the SPAST protein (p.Arg488Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;.;.;.;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;.;D;.;.;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;.;D;.;.;.;.;.
Sift4G
Pathogenic
D;D;D;.;.;.;.;.
Polyphen
D;D;.;.;.;.;.;.
Vest4
MutPred
Loss of disorder (P = 0.0253);Loss of disorder (P = 0.0253);.;.;.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at