13-23330159-T-G

Variant names:

Variant summary

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

The NM_014363.6(SACS):c.13717A>C(p.Asn4573His) variant causes a missense change. The variant allele was found at a frequency of 0.00441 in 1,613,956 control chromosomes in the GnomAD database, including 21 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 0.0033 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0045 ( 18 hom. )

Consequence

SACS
NM_014363.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4B:12

Conservation

PhyloP100: 6.24

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0107293725).

BP6

Variant 13-23330159-T-G is Benign according to our data. Variant chr13-23330159-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193707.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Benign=2, Likely_benign=9, Likely_pathogenic=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00326 (496/152340) while in subpopulation AMR AF= 0.00653 (100/15308). AF 95% confidence interval is 0.0055. There are 3 homozygotes in gnomad4. There are 238 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SACS	NM_014363.6 link	c.13717A>C	p.Asn4573His	missense_variant	Exon 10 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.13717A>C	p.Asn4573His	missense_variant	Exon 10 of 10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.00326

AC:

497

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00654

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000941

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00497

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00318

AC:

799

AN:

250932

Hom.:

AF XY:

0.00316

AC XY:

428

AN XY:

135630

show subpopulations

Gnomad AFR exome

AF:

0.000677

Gnomad AMR exome

AF:

0.00336

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000654

Gnomad FIN exome

AF:

0.00129

Gnomad NFE exome

AF:

0.00518

Gnomad OTH exome

AF:

0.00392

GnomAD4 exome

AF:

0.00453

AC:

6614

AN:

1461616

Hom.:

Cov.:

AF XY:

0.00442

AC XY:

3217

AN XY:

727114

show subpopulations

Gnomad4 AFR exome

AF:

0.000627

Gnomad4 AMR exome

AF:

0.00369

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000684

Gnomad4 FIN exome

AF:

0.00135

Gnomad4 NFE exome

AF:

0.00541

Gnomad4 OTH exome

AF:

0.00356

GnomAD4 genome

AF:

0.00326

AC:

496

AN:

152340

Hom.:

Cov.:

AF XY:

0.00319

AC XY:

238

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000770

Gnomad4 AMR

AF:

0.00653

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000941

Gnomad4 NFE

AF:

0.00497

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00482

Hom.:

Bravo

AF:

0.00358

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00315

AC:

382

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00698

EpiControl

AF:

0.00652

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia

Pathogenic:1Uncertain:2Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Aug 10, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	May 04, 2023	European Non-Finnish population allele frequency is 0.4833% (rs34382952, 655/128756 alleles, 2 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as LIKELY BENIGN. Following criteria are met: BS1 -
Benign, criteria provided, single submitter	clinical testing	Counsyl	May 23, 2018	- -
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 specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 16, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 09, 2024	Variant summary: SACS c.13717A>C (p.Asn4573His) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0044 in 1613956 control chromosomes, predominantly at a frequency of 0.0054 within the Non-Finnish European subpopulation in the gnomAD database (v.4.1), including 20 homozygotes. This suggests the variant is likely a benign polymorphism. c.13717A>C has been reported in the literature, primarily in the heterozygous state and in settings of multigene panel testing, in individuals affected with ataxias and other movement disorders, without strong evidence for causality (e.g. Vermeer_2009, Fogel_2012, Morais_2017, Martinez-Rubio_2022, OGorman_2019). These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22287014, 36233161, 28832565, 31519934, 19779133). ClinVar contains an entry for this variant (Variation ID: 193707). Based on the evidence outlined above, the variant was classified as likely benign -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 29, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Uncertain:1Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2025	SACS: BS2 -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2021	This variant is associated with the following publications: (PMID: 23280630, 22162184, 22287014, 19779133, 28832565) -

Hereditary spastic paraplegia

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	research	Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde	Mar 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Dec 04, 2020	- -

Spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 23, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

.;T

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.083

MetaRNN

Benign

0.011

T;T

MetaSVM

Uncertain

0.33

MutationAssessor

Benign

-0.34

.;N

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.0

N;N

REVEL

Uncertain

0.41

Sift

Benign

0.056

T;D

Sift4G

Uncertain

0.014

D;D

Polyphen

0.98

.;D

Vest4

0.38

MVP

0.87

ClinPred

0.012

GERP RS

5.8

Varity_R

0.72

gMVP

0.49

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