rs36061856

chr13-23332894-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_014363.6(SACS):c.10982C>T(p.Ala3661Val) variant causes a missense change. The variant allele was found at a frequency of 0.000777 in 1,613,856 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A3661T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0019 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (0 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7
• Conservation: PhyloP100: 6.51

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009445995).
• BP6: Variant 13-23332894-G-A is Benign according to our data. Variant chr13-23332894-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 212109.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4, Benign=1}. Variant chr13-23332894-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6	c.10982C>T	p.Ala3661Val	missense_variant	10/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.10982C>T	p.Ala3661Val	missense_variant	10/10	5	NM_014363.6	P1

Frequencies

GnomAD3 genomes AF: 0.00187 AC: 285 AN: 152192 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00451

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000992 AC: 248 AN: 249986 Hom.: 1 AF XY: 0.000938 AC XY: 127 AN XY: 135406

Gnomad AFR exome AF: 0.00493

Gnomad AMR exome AF: 0.00113

Gnomad ASJ exome AF: 0.00219

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.000823

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.000662 AC: 967 AN: 1461546 Hom.: 0 Cov.: 35 AF XY: 0.000653 AC XY: 475 AN XY: 727054

Gnomad4 AFR exome AF: 0.00388

Gnomad4 AMR exome AF: 0.00103

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.000220

Gnomad4 FIN exome AF: 0.000113

Gnomad4 NFE exome AF: 0.000567

Gnomad4 OTH exome AF: 0.000960

GnomAD4 genome AF: 0.00188 AC: 287 AN: 152310 Hom.: 2 Cov.: 33 AF XY: 0.00177 AC XY: 132 AN XY: 74484

Gnomad4 AFR AF: 0.00450

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00102 Hom.: 1

Bravo AF: 0.00217

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00499 AC: 22

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00116 AC: 141

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00142

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 18, 2018	This variant is associated with the following publications: (PMID: 29220673, 29915382) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 30, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2020	- -

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 24, 2022	Variant summary: SACS c.10982C>T (p.Ala3661Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0011 in 281386 control chromosomes with 2 homozygotes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (0.0011 vs 0.0079), allowing no conclusion about variant significance. c.10982C>T has been reported in the literature in at least one compound heterozygous individual affected with Spastic Paraplegia (Sun_2019). The variant was also found occuring in one compound heterozygous individual affected with intellectual disability (Martin_2017), however, this individual also carried a de novo variant in GRIA4 c.2090G>C [p.Arg697Pro]. GRIA4 associated neurodevelopmental disorders are autosomal dominant (OMIM #617864), and the authors conclude this GRIA4 variant was the cause of the patients phenotype. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters have assessed the variant since 2014: two classified the variant as VUS, six as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 17, 2014	- -

Spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	20
Dann	Uncertain	1.0
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.0094	T;T
MetaSVM	Uncertain	-0.15	T
MutationTaster	Benign	0.68	N;N;N
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.19	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.092	T;T
Sift4G	Uncertain	0.035	D;D
Polyphen		0.95	.;P
Vest4		0.36
MVP		0.89
ClinPred		0.019	T
GERP RS		6.0
Varity_R		0.059
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

Other links and lift over

dbSNP: rs36061856; hg19: chr13-23907033; COSMIC: COSV104428907;