13-23333770-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014363.6(SACS):c.10106T>C(p.Val3369Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,613,526 control chromosomes in the GnomAD database, including 58,024 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V3369G) has been classified as Benign.

Frequency

Genomes: 𝑓 0.23 ( 4559 hom., cov: 32)

Exomes 𝑓: 0.27 ( 53465 hom. )

Consequence

SACS
NM_014363.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 9.32

Publications

35 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023599565).

BP6

Variant 13-23333770-A-G is Benign according to our data. Variant chr13-23333770-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130199.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.34 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SACS	NM_014363.6 link	c.10106T>C	p.Val3369Ala	missense_variant	Exon 10 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.10106T>C	p.Val3369Ala	missense_variant	Exon 10 of 10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34366

AN:

151978

Hom.:

4556

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0908

Gnomad AMI

AF:

0.165

Gnomad AMR

AF:

0.325

Gnomad ASJ

AF:

0.401

Gnomad EAS

AF:

0.339

Gnomad SAS

AF:

0.356

Gnomad FIN

AF:

0.236

Gnomad MID

AF:

0.301

Gnomad NFE

AF:

0.258

Gnomad OTH

AF:

0.254

GnomAD2 exomes

AF:

0.287

AC:

71875

AN:

250816

AF XY:

0.288

show subpopulations

Gnomad AFR exome

AF:

0.0881

Gnomad AMR exome

AF:

0.387

Gnomad ASJ exome

AF:

0.402

Gnomad EAS exome

AF:

0.349

Gnomad FIN exome

AF:

0.246

Gnomad NFE exome

AF:

0.257

Gnomad OTH exome

AF:

0.278

GnomAD4 exome

AF:

0.266

AC:

388655

AN:

1461430

Hom.:

53465

Cov.:

AF XY:

0.268

AC XY:

195126

AN XY:

727006

show subpopulations

African (AFR)

AF:

0.0853

AC:

2853

AN:

33466

American (AMR)

AF:

0.378

AC:

16886

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.402

AC:

10493

AN:

26116

East Asian (EAS)

AF:

0.345

AC:

13700

AN:

39688

South Asian (SAS)

AF:

0.340

AC:

29363

AN:

86242

European-Finnish (FIN)

AF:

0.239

AC:

12762

AN:

53382

Middle Eastern (MID)

AF:

0.326

AC:

1879

AN:

5768

European-Non Finnish (NFE)

AF:

0.256

AC:

284963

AN:

1111696

Other (OTH)

AF:

0.261

AC:

15756

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

17807

35613

53420

71226

89033

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

9802

19604

29406

39208

49010

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.226

AC:

34381

AN:

152096

Hom.:

4559

Cov.:

AF XY:

0.231

AC XY:

17200

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.0909

AC:

3774

AN:

41522

American (AMR)

AF:

0.326

AC:

4972

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.401

AC:

1389

AN:

3464

East Asian (EAS)

AF:

0.340

AC:

1758

AN:

5176

South Asian (SAS)

AF:

0.354

AC:

1707

AN:

4818

European-Finnish (FIN)

AF:

0.236

AC:

2493

AN:

10568

Middle Eastern (MID)

AF:

0.303

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.258

AC:

17509

AN:

67976

Other (OTH)

AF:

0.257

AC:

540

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1294

2588

3881

5175

6469

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

368

736

1104

1472

1840

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.254

Hom.:

14881

Bravo

AF:

0.229

TwinsUK

AF:

0.251

AC:

932

ALSPAC

AF:

0.252

AC:

972

ESP6500AA

AF:

0.0962

AC:

424

ESP6500EA

AF:

0.260

AC:

2236

ExAC

AF:

0.278

AC:

33688

Asia WGS

AF:

0.317

AC:

1102

AN:

3478

EpiCase

AF:

0.264

EpiControl

AF:

0.268

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

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 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 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

- -

Charlevoix-Saguenay spastic ataxia

Benign:3

Nov 19, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Spastic paraplegia

Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Dec 12, 2016

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

.;T

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D

MetaRNN

Benign

0.0024

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

.;L

PhyloP100

9.3

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.2

N;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.018

D;D

Sift4G

Uncertain

0.0090

D;D

Polyphen

0.74

.;P

Vest4

0.26

ClinPred

0.036

GERP RS

5.9

Varity_R

0.13

gMVP

0.53

Mutation Taster

=94/6

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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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