rs147099630

Variant names:

• chr13-23339410-T-C
• rs147099630
• NM_014363.6:c.4466A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1489D) 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 B:15 O:1
• Conservation: PhyloP100: 1.49

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]

ACMG classification

Our verdict: Benign. The variant received -13 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 [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212114.We mark this variant Likely_benign, oryginal submissions are: {Likely_pathogenic=2, not_provided=1, Likely_benign=4, Benign=7}. Variant chr13-23339410-T-C is described in Lovd as [Pathogenic]. Variant chr13-23339410-T-C is described in Lovd as [Likely_benign].
• 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 FAILED 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	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	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.: 9 Cov.: 33

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

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.: 36 AF XY: 0.00888 AC XY: 6437 AN XY: 724824

Gnomad4 AFR exome AF: 0.000812 AC: 27 AN: 33246

Gnomad4 AMR exome AF: 0.00279 AC: 123 AN: 44060

Gnomad4 ASJ exome AF: 0.0431 AC: 1119 AN: 25990

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39656

Gnomad4 SAS exome AF: 0.0291 AC: 2477 AN: 85152

Gnomad4 FIN exome AF: 0.00184 AC: 98 AN: 53298

Gnomad4 NFE exome AF: 0.00631 AC: 7011 AN: 1110606

Gnomad4 Remaining exome AF: 0.00953 AC: 574 AN: 60232

GnomAD4 genome AF: 0.00593 AC: 903 AN: 152332 Hom.: 9 Cov.: 33 AF XY: 0.00595 AC XY: 443 AN XY: 74490

Gnomad4 AFR AF: 0.00103 AC: 0.0010344 AN: 0.0010344

Gnomad4 AMR AF: 0.00307 AC: 0.0030723 AN: 0.0030723

Gnomad4 ASJ AF: 0.0406 AC: 0.040634 AN: 0.040634

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.0263 AC: 0.0263267 AN: 0.0263267

Gnomad4 FIN AF: 0.00169 AC: 0.001693 AN: 0.001693

Gnomad4 NFE AF: 0.00747 AC: 0.00746707 AN: 0.00746707

Gnomad4 OTH AF: 0.00568 AC: 0.00567644 AN: 0.00567644

Alfa AF: 0.00761 Hom.: 24

Bravo AF: 0.00538

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00919 AC: 79

ExAC AF: 0.00903 AC: 1096

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.00780

EpiControl AF: 0.00806

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Benign:15 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia Pathogenic:1 Benign:4 Other:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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. -

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

- -

Jun 10, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Likely 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

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

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. -

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) -

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 -

not specified Benign:4

Aug 27, 2019

Genetic Services Laboratory, University of Chicago

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 23, 2016

Eurofins Ntd Llc (ga)

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

- -

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	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	14
DANN	Benign	0.82
DEOGEN2	Benign	0.16	.;T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0088	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.49	.;N
PrimateAI	Uncertain	0.49	T
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	T
GERP RS		2.2
Varity_R		0.022
gMVP		0.18
Mutation Taster		=92/8	disease causing (ClinVar)

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

LitVar

Other links and lift over

dbSNP: rs147099630; hg19: chr13-23913549;