13-23339800-A-G

Variant names:

• chr13-23339800-A-G
• rs146451611
• NM_014363.6:c.4076T>C

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.4076T>C​(p.Met1359Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00195 in 1,613,484 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts 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. M1359R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:11
• Conservation: PhyloP100: 8.95
• Publications: 10 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.022173673).
• BP6: Variant 13-23339800-A-G is Benign according to our data. Variant chr13-23339800-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193706.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00184 (281/152344) while in subpopulation NFE AF = 0.00328 (223/68028). AF 95% confidence interval is 0.00293. There are 2 homozygotes in GnomAd4. There are 135 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014363.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	NM_014363.6	MANE Select	c.4076T>C	p.Met1359Thr	missense	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.4103T>C	p.Met1368Thr	missense	Exon 11 of 11	NP_001424265.1
	SACS	NM_001278055.2		c.3635T>C	p.Met1212Thr	missense	Exon 8 of 8	NP_001264984.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	ENST00000382292.9	TSL:5 MANE Select	c.4076T>C	p.Met1359Thr	missense	Exon 10 of 10	ENSP00000371729.3
	SACS	ENST00000455470.6	TSL:1	c.2431+1645T>C		intron	N/A	ENSP00000406565.2
	SACS	ENST00000682944.1		c.4103T>C	p.Met1368Thr	missense	Exon 11 of 11	ENSP00000507173.1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 281 AN: 152226 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00424

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00328

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00194 AC: 486 AN: 250662 AF XY: 0.00188

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00325

Gnomad NFE exome AF: 0.00343

Gnomad OTH exome AF: 0.00262

GnomAD4 exome AF: 0.00196 AC: 2858 AN: 1461140 Hom.: 6 Cov.: 36 AF XY: 0.00193 AC XY: 1404 AN XY: 726778

African (AFR) AF: 0.000120 AC: 4 AN: 33444

American (AMR) AF: 0.000179 AC: 8 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 86156

European-Finnish (FIN) AF: 0.00450 AC: 240 AN: 53380

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00227 AC: 2520 AN: 1111606

Other (OTH) AF: 0.00134 AC: 81 AN: 60374

GnomAD4 genome AF: 0.00184 AC: 281 AN: 152344 Hom.: 2 Cov.: 32 AF XY: 0.00181 AC XY: 135 AN XY: 74504

African (AFR) AF: 0.000120 AC: 5 AN: 41576

American (AMR) AF: 0.000196 AC: 3 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00424 AC: 45 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00328 AC: 223 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00243 Hom.: 3

Bravo AF: 0.00128

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00182 AC: 7

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00213 AC: 258

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00180

EpiControl AF: 0.00172

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:5

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SACS: PP3, BS1, BS2

Apr 03, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 04, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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

Jan 20, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 02, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Charlevoix-Saguenay spastic ataxia Uncertain:1 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 23, 2017

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 15, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Uncertain:1 Benign:1

Feb 14, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SACS c.4076T>C (p.Met1359Thr) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 282066 control chromosomes in the gnomAD database, including 4 homozygotes. c.4076T>C has been reported in the literature in individuals affected with adult-onset sporadic ataxia and four compound heterozygous siblings affected with a milder autosomal recessive spastic ataxia of Charlevoix-Saguenay (Fogel_2012, Palmio_2016, Lipponen_2021). These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 11 ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=4), likely benign (n=6) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign.

Apr 04, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Spastic paraplegia Benign:1

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SACS-related disorder Benign:1

Oct 30, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Hereditary spastic paraplegia Benign:1

Oct 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	20
DANN	Benign	0.92
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.044
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.022	T
MetaSVM	Uncertain	0.046	D
MutationAssessor	Benign	1.8	L
PhyloP100		8.9
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.41	N
REVEL	Uncertain	0.36
Sift	Benign	0.20	T
Sift4G	Uncertain	0.0060	D
Polyphen		0.077	B
Vest4		0.68
MVP		0.78
ClinPred		0.099	T
GERP RS		6.1
Varity_R		0.18
gMVP		0.61
Mutation Taster		=60/40	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

Other links and lift over

dbSNP: rs146451611; hg19: chr13-23913939;