rs41315020

chr13-23355703-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_014363.6(SACS):c.909A>G(p.Ala303=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,614,186 control chromosomes in the GnomAD database, including 1,675 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (150 hom., cov: 33)
  • Exomes 𝑓: 0.040 (1525 hom.)
• Consequence: SACS NM_014363.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.926

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 13-23355703-T-C is Benign according to our data. Variant chr13-23355703-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 260401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23355703-T-C is described in Lovd as [Benign]. Variant chr13-23355703-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.926 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6	c.909A>G	p.Ala303=	synonymous_variant	8/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.909A>G	p.Ala303=	synonymous_variant	8/10	5	NM_014363.6	P1

Frequencies

GnomAD3 genomes AF: 0.0341 AC: 5191 AN: 152194 Hom.: 151 Cov.: 33

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0235

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.142

Gnomad SAS AF: 0.0213

Gnomad FIN AF: 0.0351

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0383

Gnomad OTH AF: 0.0440

GnomAD3 exomes AF: 0.0372 AC: 9355 AN: 251402 Hom.: 343 AF XY: 0.0369 AC XY: 5013 AN XY: 135868

Gnomad AFR exome AF: 0.0193

Gnomad AMR exome AF: 0.0119

Gnomad ASJ exome AF: 0.0246

Gnomad EAS exome AF: 0.152

Gnomad SAS exome AF: 0.0142

Gnomad FIN exome AF: 0.0320

Gnomad NFE exome AF: 0.0372

Gnomad OTH exome AF: 0.0372

GnomAD4 exome AF: 0.0402 AC: 58778 AN: 1461874 Hom.: 1525 Cov.: 34 AF XY: 0.0394 AC XY: 28664 AN XY: 727240

Gnomad4 AFR exome AF: 0.0188

Gnomad4 AMR exome AF: 0.0131

Gnomad4 ASJ exome AF: 0.0251

Gnomad4 EAS exome AF: 0.113

Gnomad4 SAS exome AF: 0.0159

Gnomad4 FIN exome AF: 0.0328

Gnomad4 NFE exome AF: 0.0419

Gnomad4 OTH exome AF: 0.0438

GnomAD4 genome AF: 0.0341 AC: 5191 AN: 152312 Hom.: 150 Cov.: 33 AF XY: 0.0342 AC XY: 2549 AN XY: 74470

Gnomad4 AFR AF: 0.0195

Gnomad4 AMR AF: 0.0235

Gnomad4 ASJ AF: 0.0213

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.0215

Gnomad4 FIN AF: 0.0351

Gnomad4 NFE AF: 0.0383

Gnomad4 OTH AF: 0.0430

Alfa AF: 0.0353 Hom.: 74

Bravo AF: 0.0344

Asia WGS AF: 0.0700 AC: 245 AN: 3478

EpiCase AF: 0.0379

EpiControl AF: 0.0353

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -

Charlevoix-Saguenay spastic ataxia Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

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	-0.72
Cadd	Benign	2.8
Dann	Benign	0.59

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: rs41315020; hg19: chr13-23929842; COSMIC: COSV66536779; COSMIC: COSV66536779;