rs147099630

Positions:

chr13-23339410-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_014363.6(SACS):c.4466A>G(p.Asn1489Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00771 in 1,610,306 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 0.0059 ( 9 hom., cov: 33)

Exomes 𝑓: 0.0079 ( 108 hom. )

Consequence

SACS
NM_014363.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:14O:1

Conservation

PhyloP100: 1.49

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008807957).

BP6

Variant 13-23339410-T-C is Benign according to our data. Variant chr13-23339410-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212114.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, not_provided=1, Benign=7, Likely_pathogenic=2}. Variant chr13-23339410-T-C is described in Lovd as [Pathogenic]. Variant chr13-23339410-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00593 (903/152332) while in subpopulation SAS AF= 0.0263 (127/4824). AF 95% confidence interval is 0.0226. There are 9 homozygotes in gnomad4. There are 443 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SACS	NM_014363.6 linkuse as main transcript	c.4466A>G	p.Asn1489Ser	missense_variant	10/10	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.4466A>G	p.Asn1489Ser	missense_variant	10/10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.00595

AC:

905

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.0406

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0265

Gnomad FIN

AF:

0.00169

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00747

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00940

AC:

2323

AN:

247218

Hom.:

AF XY:

0.0110

AC XY:

1470

AN XY:

133490

show subpopulations

Gnomad AFR exome

AF:

0.000866

Gnomad AMR exome

AF:

0.00272

Gnomad ASJ exome

AF:

0.0435

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0315

Gnomad FIN exome

AF:

0.00186

Gnomad NFE exome

AF:

0.00682

Gnomad OTH exome

AF:

0.00967

GnomAD4 exome

AF:

0.00790

AC:

11511

AN:

1457974

Hom.:

108

Cov.:

AF XY:

0.00888

AC XY:

6437

AN XY:

724824

show subpopulations

Gnomad4 AFR exome

AF:

0.000812

Gnomad4 AMR exome

AF:

0.00279

Gnomad4 ASJ exome

AF:

0.0431

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0291

Gnomad4 FIN exome

AF:

0.00184

Gnomad4 NFE exome

AF:

0.00631

Gnomad4 OTH exome

AF:

0.00953

GnomAD4 genome

AF:

0.00593

AC:

903

AN:

152332

Hom.:

Cov.:

AF XY:

0.00595

AC XY:

443

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00307

Gnomad4 ASJ

AF:

0.0406

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0263

Gnomad4 FIN

AF:

0.00169

Gnomad4 NFE

AF:

0.00747

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00876

Hom.:

Bravo

AF:

0.00538

TwinsUK

AF:

0.00701

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00919

AC:

ExAC

AF:

0.00903

AC:

1096

Asia WGS

AF:

0.0100

AC:

AN:

3478

EpiCase

AF:

0.00780

EpiControl

AF:

0.00806

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:14Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia

Pathogenic:1Benign:4Other:1

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Likely benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
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	- -

not provided

Uncertain:1Benign:4

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The SACS p.Asn1342Ser variant was not identified in the literature nor was it identified in Cosmic, MutDB, and LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs147099630) as "With Likely pathogenic allele". In ClinVar, there are five submissions with conflicting interpretations of pathogenicity: likely pathogenic (Lupski Lab, Baylor-Hopkins CMG,Baylor College of Medicine), benign (Invitae and EGL Genetic Diagnostics) and uncertain significance (Genetic Services Laboratory, University of Chicago). The associated conditions are: Spastic ataxia Charlevoix-Saguenay type, abnormality of brain morphology, and Spastic paraplegia. The variant was identified in control databases in 2472 of 278622 chromosomes (33 homozygous) at a frequency of 0.008872 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 440 of 10136 chromosomes (freq: 0.04341), South Asian in 924 of 29334 chromosomes (freq: 0.0315), Other in 66 of 7086 chromosomes (freq: 0.009314), European (non-Finnish) in 880 of 127810 chromosomes (freq: 0.006885), while the variant was not observed in the Latino, European (Finnish), African, and East Asian populations. The variant was also identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016). The p.Asn1342 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) do not suggest a high likelihood of impact to the protein. MutationTaster predicts an impact to the protein. However, all this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely 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	GeneDx	Oct 11, 2018	This variant is associated with the following publications: (PMID: 26539891, 27980752) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	SACS: BP4, BS1, BS2 -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 24, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 27, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

Abnormal brain morphology

Pathogenic:1

Likely pathogenic, flagged submission

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

- -

Spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 26, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.47

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.16

.;T

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.88

D;D

MetaRNN

Benign

0.0088

T;T

MetaSVM

Benign

-0.86

MutationAssessor

Benign

-0.49

.;N

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.28

N;N

REVEL

Benign

0.13

Sift

Benign

0.21

T;T

Sift4G

Benign

0.27

T;T

Polyphen

0.0

.;B

Vest4

0.48

MVP

0.56

ClinPred

0.011

GERP RS

2.2

Varity_R

0.022

gMVP

0.18

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