NM_014363.6:c.-13A>G

Variant names:

• chr13-23411252-T-C
• rs17078720
• NM_014363.6:c.-13A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_014363.6(SACS):​c.-13A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.321 in 1,595,820 control chromosomes in the GnomAD database, including 85,085 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.29 (6804 hom., cov: 33)
  • Exomes 𝑓: 0.32 (78281 hom.)
• Consequence: SACS NM_014363.6 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.418
• Publications: 14 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 13-23411252-T-C is Benign according to our data. Variant chr13-23411252-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 260389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.452 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SACS	NM_014363.6	c.-13A>G		5_prime_UTR_variant	Exon 2 of 10	ENST00000382292.9	NP_055178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9	c.-13A>G		5_prime_UTR_variant	Exon 2 of 10	5	NM_014363.6	ENSP00000371729.3

Frequencies

GnomAD3 genomes AF: 0.286 AC: 43515 AN: 151930 Hom.: 6799 Cov.: 33

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.336

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.370

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.310

GnomAD2 exomes AF: 0.327 AC: 81255 AN: 248422 AF XY: 0.335

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.239

Gnomad ASJ exome AF: 0.443

Gnomad EAS exome AF: 0.477

Gnomad FIN exome AF: 0.349

Gnomad NFE exome AF: 0.322

Gnomad OTH exome AF: 0.321

GnomAD4 exome AF: 0.324 AC: 468199 AN: 1443772 Hom.: 78281 Cov.: 29 AF XY: 0.327 AC XY: 235194 AN XY: 719386

African (AFR) AF: 0.152 AC: 5062 AN: 33232

American (AMR) AF: 0.246 AC: 10992 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 11531 AN: 25998

East Asian (EAS) AF: 0.435 AC: 17223 AN: 39568

South Asian (SAS) AF: 0.386 AC: 33121 AN: 85754

European-Finnish (FIN) AF: 0.342 AC: 18221 AN: 53352

Middle Eastern (MID) AF: 0.358 AC: 2054 AN: 5742

European-Non Finnish (NFE) AF: 0.319 AC: 350015 AN: 1095692

Other (OTH) AF: 0.334 AC: 19980 AN: 59766

GnomAD4 genome AF: 0.286 AC: 43543 AN: 152048 Hom.: 6804 Cov.: 33 AF XY: 0.294 AC XY: 21837 AN XY: 74320

African (AFR) AF: 0.157 AC: 6515 AN: 41510

American (AMR) AF: 0.286 AC: 4376 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1553 AN: 3466

East Asian (EAS) AF: 0.467 AC: 2416 AN: 5170

South Asian (SAS) AF: 0.388 AC: 1869 AN: 4822

European-Finnish (FIN) AF: 0.351 AC: 3703 AN: 10542

Middle Eastern (MID) AF: 0.381 AC: 112 AN: 294

European-Non Finnish (NFE) AF: 0.324 AC: 22041 AN: 67946

Other (OTH) AF: 0.309 AC: 652 AN: 2112

Alfa AF: 0.278 Hom.: 2784

Bravo AF: 0.274

Asia WGS AF: 0.400 AC: 1392 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 04, 2018

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SACS c.-13A>G is located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.32 in 120084 control chromosomes in the ExAC database, including 6625 homozygotes. The observed variant frequency is approximately 41 fold above the estimated maximal expected allele frequency for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay phenotype (0.0079), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.-13A>G in individuals affected with Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:2

Jul 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Charlevoix-Saguenay spastic ataxia Benign:2

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

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	-0.78
CADD	Benign	6.9
DANN	Benign	0.74
PhyloP100		0.42
Mutation Taster		=300/0	polymorphism (auto)

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: rs17078720; hg19: chr13-23985391; COSMIC: COSV66534551;