NM_014363.6:c.9981T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_014363.6(SACS):c.9981T>C(p.Ala3327Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,613,544 control chromosomes in the GnomAD database, including 152,040 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. A3327A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.36 ( 11309 hom., cov: 32)

Exomes 𝑓: 0.44 ( 140731 hom. )

Consequence

SACS
NM_014363.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.480

Publications

24 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.54).

BP6

Variant 13-23333895-A-G is Benign according to our data. Variant chr13-23333895-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 130206.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.48 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.441 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SACS	NM_014363.6 link	c.9981T>C	p.Ala3327Ala	synonymous_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.9981T>C	p.Ala3327Ala	synonymous_variant	Exon 10 of 10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.365

AC:

55449

AN:

151924

Hom.:

11304

Cov.:

show subpopulations

Gnomad AFR

AF:

0.175

Gnomad AMI

AF:

0.614

Gnomad AMR

AF:

0.415

Gnomad ASJ

AF:

0.377

Gnomad EAS

AF:

0.395

Gnomad SAS

AF:

0.397

Gnomad FIN

AF:

0.464

Gnomad MID

AF:

0.326

Gnomad NFE

AF:

0.446

Gnomad OTH

AF:

0.371

GnomAD2 exomes

AF:

0.411

AC:

102781

AN:

250164

AF XY:

0.416

show subpopulations

Gnomad AFR exome

AF:

0.167

Gnomad AMR exome

AF:

0.427

Gnomad ASJ exome

AF:

0.377

Gnomad EAS exome

AF:

0.397

Gnomad FIN exome

AF:

0.450

Gnomad NFE exome

AF:

0.442

Gnomad OTH exome

AF:

0.426

GnomAD4 exome

AF:

0.435

AC:

636406

AN:

1461502

Hom.:

140731

Cov.:

AF XY:

0.435

AC XY:

315957

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.161

AC:

5376

AN:

33468

American (AMR)

AF:

0.429

AC:

19198

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.378

AC:

9882

AN:

26118

East Asian (EAS)

AF:

0.411

AC:

16293

AN:

39690

South Asian (SAS)

AF:

0.396

AC:

34137

AN:

86244

European-Finnish (FIN)

AF:

0.449

AC:

23944

AN:

53320

Middle Eastern (MID)

AF:

0.348

AC:

2010

AN:

5768

European-Non Finnish (NFE)

AF:

0.450

AC:

499927

AN:

1111794

Other (OTH)

AF:

0.425

AC:

25639

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

22670

45340

68009

90679

113349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15002

30004

45006

60008

75010

<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:

0.365

AC:

55464

AN:

152042

Hom.:

11309

Cov.:

AF XY:

0.369

AC XY:

27425

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.175

AC:

7247

AN:

41506

American (AMR)

AF:

0.415

AC:

6334

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.377

AC:

1306

AN:

3468

East Asian (EAS)

AF:

0.395

AC:

2042

AN:

5164

South Asian (SAS)

AF:

0.397

AC:

1913

AN:

4816

European-Finnish (FIN)

AF:

0.464

AC:

4913

AN:

10590

Middle Eastern (MID)

AF:

0.327

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.446

AC:

30268

AN:

67940

Other (OTH)

AF:

0.374

AC:

789

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1694

3388

5082

6776

8470

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

538

1076

1614

2152

2690

<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:

0.403

Hom.:

23220

Bravo

AF:

0.352

Asia WGS

AF:

0.413

AC:

1438

AN:

3478

EpiCase

AF:

0.436

EpiControl

AF:

0.439

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Sep 04, 2019

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 19, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 05, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charlevoix-Saguenay spastic ataxia

Benign:3

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 19, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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

BayesDel_noAF

Benign

-0.54

CADD

Benign

5.3

(source)

DANN

Benign

0.66

PhyloP100

0.48

Mutation Taster

=100/0

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