rs61753111

Positions:

• chr13-23334030-T-C
• chr13-23334030-T-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_014363.6(SACS):​c.9846A>G​(p.Pro3282=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00382 in 1,613,892 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P3282P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0039 (19 hom.)
• Consequence: SACS NM_014363.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.50

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 13-23334030-T-C is Benign according to our data. Variant chr13-23334030-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 416834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23334030-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.5 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6	c.9846A>G	p.Pro3282=	synonymous_variant	10/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.9846A>G	p.Pro3282=	synonymous_variant	10/10	5	NM_014363.6	P1

Frequencies

GnomAD3 genomes AF: 0.00271 AC: 413 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00395

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00435

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00292 AC: 733 AN: 250882 Hom.: 1 AF XY: 0.00294 AC XY: 399 AN XY: 135578

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.00389

Gnomad NFE exome AF: 0.00468

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00393 AC: 5750 AN: 1461568 Hom.: 19 Cov.: 38 AF XY: 0.00390 AC XY: 2836 AN XY: 727090

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00248

Gnomad4 FIN exome AF: 0.00459

Gnomad4 NFE exome AF: 0.00452

Gnomad4 OTH exome AF: 0.00313

GnomAD4 genome AF: 0.00271 AC: 413 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.00256 AC XY: 191 AN XY: 74482

Gnomad4 AFR AF: 0.000697

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00145

Gnomad4 FIN AF: 0.00395

Gnomad4 NFE AF: 0.00435

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00339 Hom.: 0

Bravo AF: 0.00273

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00382

EpiControl AF: 0.00308

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 03, 2020	This variant is associated with the following publications: (PMID: 19779133) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	SACS: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 08, 2020

- -

Charlevoix-Saguenay spastic ataxia Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.30
DANN	Benign	0.73

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: rs61753111; hg19: chr13-23908169; COSMIC: COSV66546410;