rs17325713

Positions:

chr13-23354532-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_014363.6(SACS):c.2080G>A(p.Ala694Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0314 in 1,613,750 control chromosomes in the GnomAD database, including 948 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 79 hom., cov: 33)

Exomes 𝑓: 0.032 ( 869 hom. )

Consequence

SACS
NM_014363.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 6.06

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 (MetaRNN=0.0026889741).

BP6

Variant 13-23354532-C-T is Benign according to our data. Variant chr13-23354532-C-T is described in ClinVar as [Benign]. Clinvar id is 240895.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-23354532-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0244 (3719/152226) while in subpopulation NFE AF= 0.039 (2654/68000). AF 95% confidence interval is 0.0378. There are 79 homozygotes in gnomad4. There are 1721 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 79 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6 linkuse as main transcript	c.2080G>A	p.Ala694Thr	missense_variant	8/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9 linkuse as main transcript	c.2080G>A	p.Ala694Thr	missense_variant	8/10	5	NM_014363.6	P1	Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.0244

AC:

3719

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00579

Gnomad AMI

AF:

0.00220

Gnomad AMR

AF:

0.0165

Gnomad ASJ

AF:

0.0135

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00663

Gnomad FIN

AF:

0.0434

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0390

Gnomad OTH

AF:

0.0144

GnomAD3 exomes

AF:

0.0240

AC:

6022

AN:

250596

Hom.:

109

AF XY:

0.0238

AC XY:

3225

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.00428

Gnomad AMR exome

AF:

0.00934

Gnomad ASJ exome

AF:

0.00993

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00764

Gnomad FIN exome

AF:

0.0486

Gnomad NFE exome

AF:

0.0363

Gnomad OTH exome

AF:

0.0224

GnomAD4 exome

AF:

0.0322

AC:

47021

AN:

1461524

Hom.:

869

Cov.:

AF XY:

0.0319

AC XY:

23170

AN XY:

727078

show subpopulations

Gnomad4 AFR exome

AF:

0.00439

Gnomad4 AMR exome

AF:

0.00894

Gnomad4 ASJ exome

AF:

0.0101

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00828

Gnomad4 FIN exome

AF:

0.0464

Gnomad4 NFE exome

AF:

0.0372

Gnomad4 OTH exome

AF:

0.0268

GnomAD4 genome

AF:

0.0244

AC:

3719

AN:

152226

Hom.:

Cov.:

AF XY:

0.0231

AC XY:

1721

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.00578

Gnomad4 AMR

AF:

0.0165

Gnomad4 ASJ

AF:

0.0135

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00684

Gnomad4 FIN

AF:

0.0434

Gnomad4 NFE

AF:

0.0390

Gnomad4 OTH

AF:

0.0137

Alfa

AF:

0.0327

Hom.:

181

Bravo

AF:

0.0198

TwinsUK

AF:

0.0345

AC:

128

ALSPAC

AF:

0.0330

AC:

127

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0370

AC:

318

ExAC

AF:

0.0232

AC:

2817

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0323

EpiControl

AF:

0.0316

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 01, 2019	- -

Charlevoix-Saguenay spastic ataxia

Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2019	This variant is associated with the following publications: (PMID: 23280630, 22287014, 19779133) -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 08, 2016	- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 29, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

T;.;.

Eigen

Benign

0.12

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.90

D;D;D

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;.;.

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

0.21

N;.;.

REVEL

Benign

0.084

Sift

Benign

0.36

T;.;.

Sift4G

Benign

0.13

T;.;.

Polyphen

0.0010

B;.;.

Vest4

0.046

ClinPred

0.034

GERP RS

5.2

Varity_R

0.077

gMVP

0.29

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