rs3751368

chr13-23375113-G-Achr13-23375113-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014363.6(SACS):c.171+6C>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,491,360 control chromosomes in the GnomAD database, including 21,150 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1705 hom., cov: 33)
  • Exomes 𝑓: 0.17 (19445 hom.)
• Consequence: SACS NM_014363.6 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00001660
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.692

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 13-23375113-G-A is Benign according to our data. Variant chr13-23375113-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 260393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23375113-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6	c.171+6C>T		splice_donor_region_variant, intron_variant		ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.171+6C>T		splice_donor_region_variant, intron_variant		5	NM_014363.6	P1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20181 AN: 151732 Hom.: 1704 Cov.: 33

Gnomad AFR AF: 0.0477

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.0579

Gnomad SAS AF: 0.0732

Gnomad FIN AF: 0.166

Gnomad MID AF: 0.126

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.135

GnomAD3 exomes AF: 0.162 AC: 14755 AN: 91072 Hom.: 1356 AF XY: 0.153 AC XY: 7808 AN XY: 51124

Gnomad AFR exome AF: 0.0336

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.0546

Gnomad SAS exome AF: 0.0862

Gnomad FIN exome AF: 0.160

Gnomad NFE exome AF: 0.183

Gnomad OTH exome AF: 0.176

GnomAD4 exome AF: 0.166 AC: 222669 AN: 1339522 Hom.: 19445 Cov.: 32 AF XY: 0.164 AC XY: 108137 AN XY: 660346

Gnomad4 AFR exome AF: 0.0389

Gnomad4 AMR exome AF: 0.231

Gnomad4 ASJ exome AF: 0.134

Gnomad4 EAS exome AF: 0.0870

Gnomad4 SAS exome AF: 0.0829

Gnomad4 FIN exome AF: 0.157

Gnomad4 NFE exome AF: 0.178

Gnomad4 OTH exome AF: 0.148

GnomAD4 genome AF: 0.133 AC: 20184 AN: 151838 Hom.: 1705 Cov.: 33 AF XY: 0.132 AC XY: 9787 AN XY: 74218

Gnomad4 AFR AF: 0.0476

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.131

Gnomad4 EAS AF: 0.0580

Gnomad4 SAS AF: 0.0731

Gnomad4 FIN AF: 0.166

Gnomad4 NFE AF: 0.178

Gnomad4 OTH AF: 0.136

Alfa AF: 0.134 Hom.: 467

Bravo AF: 0.131

Asia WGS AF: 0.0890 AC: 306 AN: 3458

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Apr 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2018	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	6.2
Dann	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0020
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: rs3751368; hg19: chr13-23949252;