rs770866403

chr13-23340547-AT-Achr13-23340547-AT-ATT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_014363.6(SACS):c.3328del(p.Ile1110LeufsTer16) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000164 in 1,459,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: SACS NM_014363.6 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.96

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 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 424 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-23340547-AT-A is Pathogenic according to our data. Variant chr13-23340547-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 2744159.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23340547-AT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6	c.3328del	p.Ile1110LeufsTer16	frameshift_variant	10/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.3328del	p.Ile1110LeufsTer16	frameshift_variant	10/10	5	NM_014363.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000164 AC: 24 AN: 1459350 Hom.: 0 Cov.: 36 AF XY: 0.0000207 AC XY: 15 AN XY: 725934

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.000113

Gnomad4 ASJ exome AF: 0.0000769

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000700

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome Cov.: 33

Alfa AF: 0.000153 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 08, 2024

This sequence change creates a premature translational stop signal (p.Ile1110Leufs*16) in the SACS gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3470 amino acid(s) of the SACS protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SACS-related conditions. This variant disrupts a region of the SACS protein in which other variant(s) (p.Tyr4538*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs770866403; hg19: chr13-23914686;