rs41315020

Positions:

chr13-23355703-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6BP7BA1

The NM_014363.6(SACS):c.909A>G(p.Ala303Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0396 in 1,614,186 control chromosomes in the GnomAD database, including 1,675 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.034 ( 150 hom., cov: 33)

Exomes 𝑓: 0.040 ( 1525 hom. )

Consequence

SACS
NM_014363.6 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:10

Conservation

PhyloP100: -0.926

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:

SACS (HGNC:):

SACS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 13-23355703-T-C is Benign according to our data. Variant chr13-23355703-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260401.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=3, Likely_pathogenic=1}. Variant chr13-23355703-T-C is described in Lovd as [Benign]. Variant chr13-23355703-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.926 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SACS	NM_014363.6 linkuse as main transcript	c.909A>G	p.Ala303Ala	synonymous_variant	8/10	ENST00000382292.9	NP_055178.3	Q9NZJ4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9 linkuse as main transcript	c.909A>G	p.Ala303Ala	synonymous_variant	8/10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.0341

AC:

5191

AN:

152194

Hom.:

151

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0194

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0235

Gnomad ASJ

AF:

0.0213

Gnomad EAS

AF:

0.142

Gnomad SAS

AF:

0.0213

Gnomad FIN

AF:

0.0351

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0383

Gnomad OTH

AF:

0.0440

GnomAD3 exomes

AF:

0.0372

AC:

9355

AN:

251402

Hom.:

343

AF XY:

0.0369

AC XY:

5013

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.0193

Gnomad AMR exome

AF:

0.0119

Gnomad ASJ exome

AF:

0.0246

Gnomad EAS exome

AF:

0.152

Gnomad SAS exome

AF:

0.0142

Gnomad FIN exome

AF:

0.0320

Gnomad NFE exome

AF:

0.0372

Gnomad OTH exome

AF:

0.0372

GnomAD4 exome

AF:

0.0402

AC:

58778

AN:

1461874

Hom.:

1525

Cov.:

AF XY:

0.0394

AC XY:

28664

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0188

Gnomad4 AMR exome

AF:

0.0131

Gnomad4 ASJ exome

AF:

0.0251

Gnomad4 EAS exome

AF:

0.113

Gnomad4 SAS exome

AF:

0.0159

Gnomad4 FIN exome

AF:

0.0328

Gnomad4 NFE exome

AF:

0.0419

Gnomad4 OTH exome

AF:

0.0438

GnomAD4 genome

AF:

0.0341

AC:

5191

AN:

152312

Hom.:

150

Cov.:

AF XY:

0.0342

AC XY:

2549

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.0195

Gnomad4 AMR

AF:

0.0235

Gnomad4 ASJ

AF:

0.0213

Gnomad4 EAS

AF:

0.141

Gnomad4 SAS

AF:

0.0215

Gnomad4 FIN

AF:

0.0351

Gnomad4 NFE

AF:

0.0383

Gnomad4 OTH

AF:

0.0430

Alfa

AF:

0.0353

Hom.:

Bravo

AF:

0.0344

Asia WGS

AF:

0.0700

AC:

245

AN:

3478

EpiCase

AF:

0.0379

EpiControl

AF:

0.0353

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 27, 2023	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Charlevoix-Saguenay spastic ataxia

Pathogenic:1Benign:2

Likely pathogenic, criteria provided, single submitter	research	PROSPAX: an integrated multimodal progression chart in spastic ataxias, Center for Neurology; Hertie-Institute for Clinical Brain Research	Jan 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2018	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

2.8

DANN

Benign

0.59

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