rs3751368

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014363.6(SACS):c.171+6C>T variant causes a splice 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron

Scores

Splicing: ADA: 0.00001660

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.692

Variant links:

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]

SACS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
SACS	NM_014363.6 link	c.171+6C>T		splice_region_variant, intron_variant	Intron 3 of 9	ENST00000382292.9	NP_055178.3	Q9NZJ4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9 link	c.171+6C>T		splice_region_variant, intron_variant	Intron 3 of 9	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.133

AC:

20181

AN:

151732

Hom.:

1704

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.164

AC XY:

108137

AN XY:

660346

show subpopulations

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.:

AF XY:

0.132

AC XY:

9787

AN XY:

74218

show subpopulations

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:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia

Benign:4

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 20, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 26, 2017

Counsyl

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Jul 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Spastic paraplegia

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over