rs146451611

chr13-23339800-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• 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:5 B:11
• Conservation: PhyloP100: 8.95

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

Verdict is Benign. Variant got -9 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 id is 193706.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=5, Benign=1}. Variant chr13-23339800-A-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6	c.4076T>C	p.Met1359Thr	missense_variant	10/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.4076T>C	p.Met1359Thr	missense_variant	10/10	5	NM_014363.6	P1

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

GnomAD3 exomes AF: 0.00194 AC: 486 AN: 250662 Hom.: 3 AF XY: 0.00188 AC XY: 255 AN XY: 135456

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 SAS 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

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.000153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00450

Gnomad4 NFE exome AF: 0.00227

Gnomad4 OTH exome AF: 0.00134

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

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00424

Gnomad4 NFE AF: 0.00328

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00248 Hom.: 0

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:5 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2021	This variant is associated with the following publications: (PMID: 27980752) -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 02, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	SACS: BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 20, 2022	- -

Charlevoix-Saguenay spastic ataxia Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 15, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 14, 2018	The SACs c.4076T>C (p.Met1359Thr) missense variant has been reported in two studies in which it is found in a total of five patients with ARSACS, including in four siblings in a compound heterozygous state and in one unrelated individual in a heterozygous state with no second variant identified (Fogel et al. 2012; Palmio et al. 2016). Palmio et al. (2016) studied a Finnish family with a milder phenotype of ARSACS that presented in early adulthood. The p.Met1359Thr variant was found in trans with a double allele containing two missense variants. The three variants together segregated with disease in four affected siblings. Based on segregation analysis, the p.Met1359Thr variant was considered a disease-causing allele. Control data are unavailable for this variant which is reported at a frequency of 0.00356 in the European (non-Finnish) population of the Exome Aggregate Consortium. Based on the evidence, the p.Met1359Thr variant is classified as a variant of unknown significance but suspicious for pathogenicity for ARSACS. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 04, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 14, 2023	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. -

Spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

SACS-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 30, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

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
Eigen	Benign	0.044
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.022	T;T
MetaSVM	Uncertain	0.046	D
MutationTaster	Benign	0.60	N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.41	N;N
REVEL	Uncertain	0.36
Sift	Benign	0.20	T;T
Sift4G	Uncertain	0.0060	D;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

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: rs146451611; hg19: chr13-23913939;