13-23411252-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.418

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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. Variant chr13-23411252-T-C is described in Lovd as [Benign].

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 link	c.-13A>G		5_prime_UTR_variant	Exon 2 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.-13A>G		5_prime_UTR_variant	Exon 2 of 10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.286

AC:

43515

AN:

151930

Hom.:

6799

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.327

AC:

81255

AN:

248422

Hom.:

13997

AF XY:

0.335

AC XY:

45204

AN XY:

135008

show subpopulations

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 SAS exome

AF:

0.390

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.:

AF XY:

0.327

AC XY:

235194

AN XY:

719386

show subpopulations

Gnomad4 AFR exome

AF:

0.152

Gnomad4 AMR exome

AF:

0.246

Gnomad4 ASJ exome

AF:

0.444

Gnomad4 EAS exome

AF:

0.435

Gnomad4 SAS exome

AF:

0.386

Gnomad4 FIN exome

AF:

0.342

Gnomad4 NFE exome

AF:

0.319

Gnomad4 OTH exome

AF:

0.334

GnomAD4 genome

AF:

0.286

AC:

43543

AN:

152048

Hom.:

6804

Cov.:

AF XY:

0.294

AC XY:

21837

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.157

Gnomad4 AMR

AF:

0.286

Gnomad4 ASJ

AF:

0.448

Gnomad4 EAS

AF:

0.467

Gnomad4 SAS

AF:

0.388

Gnomad4 FIN

AF:

0.351

Gnomad4 NFE

AF:

0.324

Gnomad4 OTH

AF:

0.309

Alfa

AF:

0.254

Hom.:

1451

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

LINK: link

Submissions by phenotype

not specified

Benign:4

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. -

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

- -

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over