rs750218565

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000315285.9(SPAST):​c.280G>A​(p.Gly94Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,449,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

SPAST
ENST00000315285.9 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.473
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.19762555).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SPASTNM_014946.4 linkuse as main transcriptc.280G>A p.Gly94Arg missense_variant 1/17 ENST00000315285.9 NP_055761.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SPASTENST00000315285.9 linkuse as main transcriptc.280G>A p.Gly94Arg missense_variant 1/171 NM_014946.4 ENSP00000320885 P4Q9UBP0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000920
AC:
2
AN:
217472
Hom.:
0
AF XY:
0.00000842
AC XY:
1
AN XY:
118820
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000212
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000276
AC:
4
AN:
1449000
Hom.:
0
Cov.:
35
AF XY:
0.00000278
AC XY:
2
AN XY:
719698
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000362
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378
ExAC
AF:
0.0000167
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 4 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 15, 2022This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 94 of the SPAST protein (p.Gly94Arg). 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. 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 not expected to disrupt SPAST protein function. ClinVar contains an entry for this variant (Variation ID: 572264). This variant has not been reported in the literature in individuals affected with SPAST-related conditions. This variant is present in population databases (rs750218565, gnomAD 0.002%). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.042
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
14
DANN
Benign
0.90
DEOGEN2
Benign
0.14
T;T;.;.;.;.;.;.
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.19
N
LIST_S2
Benign
0.71
.;T;T;.;T;T;T;T
M_CAP
Pathogenic
0.92
D
MetaRNN
Benign
0.20
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.46
T
MutationAssessor
Benign
0.0
N;N;N;N;.;.;.;.
MutationTaster
Benign
0.68
N;N
PrimateAI
Pathogenic
0.85
D
PROVEAN
Benign
0.54
N;.;N;.;.;.;.;.
REVEL
Uncertain
0.33
Sift
Benign
0.60
T;.;T;.;.;.;.;.
Sift4G
Benign
0.23
T;T;T;.;.;.;.;.
Polyphen
0.0
B;B;.;.;.;.;.;.
Vest4
0.13
MutPred
0.22
Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);Gain of MoRF binding (P = 0.013);.;.;
MVP
0.27
MPC
0.15
ClinPred
0.057
T
GERP RS
-0.88
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.046
gMVP
0.14

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: rs750218565; hg19: chr2-32289180; API