NM_014363.6:c.4466A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014363.6(SACS):c.4466A>G(p.Asn1489Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 1,610,306 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. N1489H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0059 ( 9 hom., cov: 33)

Exomes 𝑓: 0.0079 ( 108 hom. )

Consequence

SACS
NM_014363.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:2B:16O:1

Conservation

PhyloP100: 1.49

Publications

10 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=0.008807957).

BP6

Variant 13-23339410-T-C is Benign according to our data. Variant chr13-23339410-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00593 (903/152332) while in subpopulation SAS AF = 0.0263 (127/4824). AF 95% confidence interval is 0.0226. There are 9 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SACS	NM_014363.6 link	c.4466A>G	p.Asn1489Ser	missense_variant	Exon 10 of 10	ENST00000382292.9	NP_055178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9 link	c.4466A>G	p.Asn1489Ser	missense_variant	Exon 10 of 10	5	NM_014363.6	ENSP00000371729.3

Frequencies

GnomAD3 genomes

AF:

0.00595

AC:

905

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.0406

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0265

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00747

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00940

AC:

2323

AN:

247218

AF XY:

0.0110

show subpopulations

Gnomad AFR exome

AF:

0.000866

Gnomad AMR exome

AF:

0.00272

Gnomad ASJ exome

AF:

0.0435

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00186

Gnomad NFE exome

AF:

0.00682

Gnomad OTH exome

AF:

0.00967

GnomAD4 exome

AF:

0.00790

AC:

11511

AN:

1457974

Hom.:

108

Cov.:

AF XY:

0.00888

AC XY:

6437

AN XY:

724824

show subpopulations

African (AFR)

AF:

0.000812

AC:

AN:

33246

American (AMR)

AF:

0.00279

AC:

123

AN:

44060

Ashkenazi Jewish (ASJ)

AF:

0.0431

AC:

1119

AN:

25990

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39656

South Asian (SAS)

AF:

0.0291

AC:

2477

AN:

85152

European-Finnish (FIN)

AF:

0.00184

AC:

AN:

53298

Middle Eastern (MID)

AF:

0.0141

AC:

AN:

5734

European-Non Finnish (NFE)

AF:

0.00631

AC:

7011

AN:

1110606

Other (OTH)

AF:

0.00953

AC:

574

AN:

60232

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

585

1171

1756

2342

2927

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

276

552

828

1104

1380

<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:

0.00593

AC:

903

AN:

152332

Hom.:

Cov.:

AF XY:

0.00595

AC XY:

443

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41570

American (AMR)

AF:

0.00307

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0406

AC:

141

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.0263

AC:

127

AN:

4824

European-Finnish (FIN)

AF:

0.00169

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00747

AC:

508

AN:

68032

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00761

Hom.:

Bravo

AF:

0.00538

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00919

AC:

ExAC

AF:

0.00903

AC:

1096

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.00780

EpiControl

AF:

0.00806

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:2Benign:16Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia

Pathogenic:1Benign:4Other:1

May 18, 2021

Pars Genome Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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:flagged submission

Collection Method:research

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 10, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:5

Aug 27, 2019

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 23, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 15, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:5

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

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 06, 2025

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SACS p.Asn1489Ser variant was not identified in the literature. The p.Asn1489Ser variant was identified in dbSNP (ID: rs147099630) and ClinVar (classified as benign 7X by GeneDx, Labcorp Genetics (formerly Invitae), Labcorp and 5 other submitters; likely benign 4X; likely pathogenic 1X). The variant was identified in control databases in 12414 of 1610306 chromosomes (117 homozygous) at a frequency of 0.007709, and was observed at the highest frequency in the Ashkenazi Jewish population in 1260 of 29460 chromosomes (freq: 0.04277) (Genome Aggregation Database April 19, 2024, v4.1.0). The p.Asn1489Ser residue is conserved in mammals and computational analyses (MUT Assesor, PolyPhen-2, SIFT, MutationTaster, Revel, FATHMM, MetaLR, DANN) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (Splice AI exome) do not predict a deleterious effect on splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SACS: BP4, BS1, BS2 -

Oct 11, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 26539891, 27980752) -

Abnormal brain morphology

Pathogenic:1

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:research

- -

Spastic paraplegia

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary spastic paraplegia

Benign:1

Apr 26, 2021

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

0.067

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.16

.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-0.49

.;N

PhyloP100

1.5

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.28

N;N

REVEL

Benign

0.13

Sift

Benign

0.21

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.0

.;B

Vest4

0.48

MVP

0.56

ClinPred

0.011

GERP RS

2.2

Varity_R

0.022

gMVP

0.18

Mutation Taster

=92/8

disease causing (ClinVar)

(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