rs876657721

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_014363.6(SACS):​c.8542_8543del​(p.Phe2848ProfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,668 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β˜…β˜…).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

SACS
NM_014363.6 frameshift

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 8.95
Variant links:
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 208 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-23335332-GAA-G is Pathogenic according to our data. Variant chr13-23335332-GAA-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 228394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SACSNM_014363.6 linkuse as main transcriptc.8542_8543del p.Phe2848ProfsTer14 frameshift_variant 10/10 ENST00000382292.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SACSENST00000382292.9 linkuse as main transcriptc.8542_8543del p.Phe2848ProfsTer14 frameshift_variant 10/105 NM_014363.6 P1Q9NZJ4-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461668
Hom.:
0
AF XY:
0.00000138
AC XY:
1
AN XY:
727132
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
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

Charlevoix-Saguenay spastic ataxia Pathogenic:2
Likely pathogenic, criteria provided, single submitterclinical testingCounsylApr 11, 2018- -
Likely pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
Autosomal recessive spastic ataxia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineAug 08, 2015The p.Phe2848fs variant in SACS has not been previously reported in individuals with clinical features of autosomal recessive spastic ataxia of Charlevoix-Sague nay (ARSACS) or in large population studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at positi on 2848 and leads to a premature termination codon 14 amino acids downstream. T his premature termination codon occurs within the last exon of the gene (exon 10 ), and is more likely to escape nonsense mediated decay (NMD). Therefore, this v ariant is predicted to result in a truncated protein that is 1718 amino acids sh orter and lacks several functional domains of the normal protein. Loss of functi on variants in the SACS gene, most of which occur in exon 10, have been reported in several patients with ARSACS (Bouhlal 2011), and animal models support a los s of function mechanism of disease (Lariviere 2015). In summary, this variant me ets our criteria to be classified as pathogenic for ARSACS in an autosomal reces sive manner (http://www.partners.org/personalizedmedicine/LMM). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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: rs876657721; hg19: chr13-23909471; API