rs374672041

chr13-23375106-G-Achr13-23375106-G-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.171+13C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00331 in 1,490,128 control chromosomes in the GnomAD database, including 70 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 0.013 (39 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (31 hom.)
• Consequence: SACS NM_014363.6 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.570

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 (BayesDel_noAF=-0.76).
• BP6: Variant 13-23375106-G-A is Benign according to our data. Variant chr13-23375106-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 260392.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=1, Uncertain_significance=1}. Variant chr13-23375106-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0131 (1986/152146) while in subpopulation AFR AF= 0.042 (1745/41530). AF 95% confidence interval is 0.0404. There are 39 homozygotes in gnomad4. There are 945 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 40 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6	c.171+13C>T		intron_variant		ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.171+13C>T		intron_variant		5	NM_014363.6	P1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1979 AN: 152040 Hom.: 40 Cov.: 33

Gnomad AFR AF: 0.0420

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.0253

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00347 AC: 313 AN: 90304 Hom.: 4 AF XY: 0.00333 AC XY: 169 AN XY: 50754

Gnomad AFR exome AF: 0.0452

Gnomad AMR exome AF: 0.00266

Gnomad ASJ exome AF: 0.0227

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000942

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00152

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00220 AC: 2940 AN: 1337982 Hom.: 31 Cov.: 30 AF XY: 0.00210 AC XY: 1387 AN XY: 659420

Gnomad4 AFR exome AF: 0.0461

Gnomad4 AMR exome AF: 0.00315

Gnomad4 ASJ exome AF: 0.0235

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000490

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000634

Gnomad4 OTH exome AF: 0.00584

GnomAD4 genome AF: 0.0131 AC: 1986 AN: 152146 Hom.: 39 Cov.: 33 AF XY: 0.0127 AC XY: 945 AN XY: 74394

Gnomad4 AFR AF: 0.0420

Gnomad4 AMR AF: 0.00530

Gnomad4 ASJ AF: 0.0253

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.00578 Hom.: 4

Bravo AF: 0.0143

Asia WGS AF: 0.00232 AC: 8 AN: 3466

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 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. -

Spastic paraplegia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	3.5
Dann	Benign	0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs374672041; hg19: chr13-23949245;