rs121908519

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_014946.4(SPAST):​c.1335C>A​(p.Ser445Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SPAST
NM_014946.4 missense

Scores

12
4
3

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.997
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 Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978
PP5
Variant 2-32136890-C-A is Pathogenic according to our data. Variant chr2-32136890-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 5676.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
SPASTNM_014946.4 linkuse as main transcriptc.1335C>A p.Ser445Arg 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.1335C>A p.Ser445Arg missense_variant 11/171 NM_014946.4 ENSP00000320885 P4Q9UBP0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460822
Hom.:
0
Cov.:
30
AF XY:
0.00000138
AC XY:
1
AN XY:
726770
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:
9.00e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 4 Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMJul 11, 2006- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.39
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.91
D;D;.;.;.;.;.;.
Eigen
Uncertain
0.26
Eigen_PC
Benign
0.19
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Pathogenic
0.99
.;D;D;.;D;D;D;D
M_CAP
Pathogenic
0.36
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.69
D
MutationAssessor
Benign
1.7
L;L;.;.;.;.;.;.
MutationTaster
Benign
1.0
A;A
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-5.0
D;.;D;.;.;.;.;.
REVEL
Pathogenic
0.84
Sift
Pathogenic
0.0
D;.;D;.;.;.;.;.
Sift4G
Pathogenic
0.0010
D;D;D;.;.;.;.;.
Polyphen
1.0
D;D;.;.;.;.;.;.
Vest4
0.98
MutPred
0.92
Loss of phosphorylation at S445 (P = 0.0626);Loss of phosphorylation at S445 (P = 0.0626);.;.;.;.;.;.;
MVP
1.0
MPC
2.4
ClinPred
1.0
D
GERP RS
-0.043
Varity_R
0.99
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: rs121908519; hg19: chr2-32361959; API