rs1553318223

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_014946.4(SPAST):​c.1348A>G​(p.Arg450Gly) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R450S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

SPAST
NM_014946.4 missense

Scores

13
5
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.57
Variant links:
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 16 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
Variant 2-32136903-A-G is Pathogenic according to our data. Variant chr2-32136903-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 536442.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SPASTNM_014946.4 linkuse as main transcriptc.1348A>G p.Arg450Gly missense_variant 11/17 ENST00000315285.9 NP_055761.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SPASTENST00000315285.9 linkuse as main transcriptc.1348A>G p.Arg450Gly missense_variant 11/171 NM_014946.4 ENSP00000320885 P4Q9UBP0-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 4 Pathogenic:3
Pathogenic, criteria provided, single submitterclinical testingConcord Molecular Medicine Laboratory, Concord Repatriation General HospitalFeb 20, 2024This variant has been detected in an affected individual and segregation study on both parents confirmed the variant to be de novo. In silico analysis by REVEL suggests this variant to be damaging (REVEL: 0.898). It is located in the critical core ATPase AAA-type domain (IPR003959) and in a mutational hot spot. The variation is absent in control population (GnomAD). Another amino acid changes in the same residue location has been observed in individuals with HSP (PMID: 21546041). -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 09, 2022This missense change has been observed in individuals with clinical features of spastic paraplegia (Invitae). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg450 amino acid residue in SPAST. Other variant(s) that disrupt this residue have been observed in individuals with SPAST-related conditions (PMID: 21546041; Invitae), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SPAST protein function. ClinVar contains an entry for this variant (Variation ID: 536442). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 450 of the SPAST protein (p.Arg450Gly). -
Likely pathogenic, criteria provided, single submitterclinical testingGreenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic CenterDec 01, 2021PM5, PM2, PM1, PP3 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.48
D
BayesDel_noAF
Pathogenic
0.45
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.93
D;D;.;.;.;.;.;.
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Pathogenic
0.99
.;D;D;.;D;D;D;D
M_CAP
Pathogenic
0.69
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.90
D
MutationAssessor
Uncertain
2.3
M;M;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-6.9
D;.;D;.;.;.;.;.
REVEL
Pathogenic
0.90
Sift
Pathogenic
0.0
D;.;D;.;.;.;.;.
Sift4G
Pathogenic
0.0
D;D;D;.;.;.;.;.
Polyphen
1.0
D;D;.;.;.;.;.;.
Vest4
0.89
MutPred
0.91
Loss of stability (P = 0.0295);Loss of stability (P = 0.0295);.;.;.;.;.;.;
MVP
0.99
MPC
2.5
ClinPred
1.0
D
GERP RS
3.1
Varity_R
0.98
gMVP
0.98

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1553318223; hg19: chr2-32361972; API