rs1555251963

chr13-23337884-TAG-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PP5_Moderate

The NM_014363.6(SACS):c.5990_5991del(p.Ser1997TyrfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. S1997S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: SACS NM_014363.6 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.62

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 10 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 292 pathogenic variants in the truncated region.
• PP5: Variant 13-23337884-TAG-T is Pathogenic according to our data. Variant chr13-23337884-TAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555886.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr13-23337884-TAG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6	c.5990_5991del	p.Ser1997TyrfsTer3	frameshift_variant	10/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.5990_5991del	p.Ser1997TyrfsTer3	frameshift_variant	10/10	5	NM_014363.6	P1

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

Jan 02, 2018

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Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs1555251963; hg19: chr13-23912023;