rs41315020

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BA1

The NM_014363.6(SACS):c.909A>G(p.Ala303Ala) 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.034 ( 150 hom., cov: 33)

Exomes 𝑓: 0.040 ( 1525 hom. )

Consequence

SACS
NM_014363.6 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:10

Conservation

PhyloP100: -0.926

Publications

8 publications found

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 Gene-Disease associations (from GenCC):

Charlevoix-Saguenay spastic ataxia
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health

SACS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.066).

BP6

Variant 13-23355703-T-C is Benign according to our data. Variant chr13-23355703-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260401.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

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 rank	MANE	Protein	UniProt
SACS	NM_014363.6 link	c.909A>G	p.Ala303Ala	synonymous_variant	Exon 8 of 10	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.909A>G	p.Ala303Ala	synonymous_variant	Exon 8 of 10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.0341

AC:

5191

AN:

152194

Hom.:

151

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.0372

AC:

9355

AN:

251402

AF XY:

0.0369

show subpopulations

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 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.:

AF XY:

0.0394

AC XY:

28664

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0188

AC:

630

AN:

33480

American (AMR)

AF:

0.0131

AC:

585

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0251

AC:

656

AN:

26136

East Asian (EAS)

AF:

0.113

AC:

4486

AN:

39700

South Asian (SAS)

AF:

0.0159

AC:

1370

AN:

86256

European-Finnish (FIN)

AF:

0.0328

AC:

1753

AN:

53420

Middle Eastern (MID)

AF:

0.0156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0419

AC:

46562

AN:

1111994

Other (OTH)

AF:

0.0438

AC:

2646

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

3407

6814

10222

13629

17036

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0341

AC:

5191

AN:

152312

Hom.:

150

Cov.:

AF XY:

0.0342

AC XY:

2549

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.0195

AC:

809

AN:

41564

American (AMR)

AF:

0.0235

AC:

359

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0213

AC:

AN:

3468

East Asian (EAS)

AF:

0.141

AC:

733

AN:

5182

South Asian (SAS)

AF:

0.0215

AC:

104

AN:

4828

European-Finnish (FIN)

AF:

0.0351

AC:

373

AN:

10612

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0383

AC:

2604

AN:

68036

Other (OTH)

AF:

0.0430

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

261

522

783

1044

1305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0375

Hom.:

300

Bravo

AF:

0.0344

Asia WGS

AF:

0.0700

AC:

245

AN:

3478

EpiCase

AF:

0.0379

EpiControl

AF:

0.0353

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Oct 27, 2023

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charlevoix-Saguenay spastic ataxia

Pathogenic:1Benign:2

Jan 01, 2022

PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 22, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

-0.72

CADD

Benign

2.8

(source)

DANN

Benign

0.59

PhyloP100

-0.93

Mutation Taster

=288/12

polymorphism (auto)

(source)

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

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rs41315020

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over