rs35256065

Positions:

• chr13-23332980-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014363.6(SACS):​c.10896A>G​(p.Ile3632Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,613,882 control chromosomes in the GnomAD database, including 14 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0052 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (7 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 1.00

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010038793).
• BP6: Variant 13-23332980-T-C is Benign according to our data. Variant chr13-23332980-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 311508.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}. Variant chr13-23332980-T-C is described in Lovd as [Benign]. Variant chr13-23332980-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00524 (798/152328) while in subpopulation AFR AF= 0.0179 (743/41582). AF 95% confidence interval is 0.0168. There are 7 homozygotes in gnomad4. There are 366 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6	c.10896A>G	p.Ile3632Met	missense_variant	10/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.10896A>G	p.Ile3632Met	missense_variant	10/10	5	NM_014363.6	P1

Frequencies

GnomAD3 genomes AF: 0.00523 AC: 796 AN: 152210 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00146 AC: 366 AN: 250662 Hom.: 5 AF XY: 0.00108 AC XY: 147 AN XY: 135534

Gnomad AFR exome AF: 0.0185

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000819

GnomAD4 exome AF: 0.000608 AC: 889 AN: 1461554 Hom.: 7 Cov.: 35 AF XY: 0.000508 AC XY: 369 AN XY: 727070

Gnomad4 AFR exome AF: 0.0184

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00524 AC: 798 AN: 152328 Hom.: 7 Cov.: 33 AF XY: 0.00491 AC XY: 366 AN XY: 74496

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.000795 Hom.: 0

Bravo AF: 0.00591

ESP6500AA AF: 0.0154 AC: 68

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00185 AC: 225

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia Uncertain:1 Benign:2

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	Jan 12, 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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:3

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	Jun 16, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	.;T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.92	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	2.0	.;M
MutationTaster	Benign	0.69	N;N;N
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.19	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.092	T;T
Sift4G	Uncertain	0.0070	D;D
Polyphen		0.97	.;D
Vest4		0.76
MVP		0.78
ClinPred		0.031	T
GERP RS		2.2
Varity_R		0.097
gMVP		0.52

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: rs35256065; hg19: chr13-23907119; COSMIC: COSV99063589;