rs1057517123
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_014363.6(SACS):c.13283_13284insA(p.Tyr4428Ter) variant causes a stop gained, frameshift change. The variant allele was found at a frequency of 0.00000205 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y4428Y) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
SACS
NM_014363.6 stop_gained, frameshift
NM_014363.6 stop_gained, frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.13
Genes affected
SACS (HGNC:10519): (sacsin molecular chaperone) This gene encodes the sacsin protein, which includes a UbL domain at the N-terminus, a DnaJ domain, and a HEPN domain at the C-terminus. The gene is highly expressed in the central nervous system, also found in skin, skeletal muscles and at low levels in the pancreas. This gene includes a very large exon spanning more than 12.8 kb. Mutations in this gene result in autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disorder characterized by early-onset cerebellar ataxia with spasticity and peripheral neuropathy. The authors of a publication on the effects of siRNA-mediated sacsin knockdown concluded that sacsin protects against mutant ataxin-1 and suggest that "the large multi-domain sacsin protein is able to recruit Hsp70 chaperone action and has the potential to regulate the effects of other ataxia proteins" (Parfitt et al., PubMed: 19208651). A pseudogene associated with this gene is located on chromosome 11. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 23 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 13-23330592-G-GT is Pathogenic according to our data. Variant chr13-23330592-G-GT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 371248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SACS | NM_014363.6 | c.13283_13284insA | p.Tyr4428Ter | stop_gained, frameshift_variant | 10/10 | ENST00000382292.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SACS | ENST00000382292.9 | c.13283_13284insA | p.Tyr4428Ter | stop_gained, frameshift_variant | 10/10 | 5 | NM_014363.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461688Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727166
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33
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727166
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GnomAD4 genome ? Cov.: 33
GnomAD4 genome
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33
Bravo
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 16, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 06, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 08, 2016 | - - |
Spastic paraplegia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 16, 2022 | ClinVar contains an entry for this variant (Variation ID: 371248). This variant has not been reported in the literature in individuals affected with SACS-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr4428*) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 152 amino acid(s) of the SACS protein. This variant disrupts the p.Asn4549 amino acid residue in SACS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15156359, 21507954). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at