rs9510730

Positions:

• chr13-23420124-G-A
• chr13-23420124-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014363.6(SACS):​c.-501-8384C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.781 in 152,072 control chromosomes in the GnomAD database, including 46,675 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.78 (46675 hom., cov: 32)
• Consequence: SACS NM_014363.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.39

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-AS1 (HGNC:39835): (SACS antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.893 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6	c.-501-8384C>T		intron_variant		ENST00000382292.9
SACS-AS1	NR_103450.1	n.331+823G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.-501-8384C>T		intron_variant		5	NM_014363.6	P1
SACS-AS1	ENST00000443092.2	n.331+823G>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.781 AC: 118638 AN: 151954 Hom.: 46630 Cov.: 32

Gnomad AFR AF: 0.718

Gnomad AMI AF: 0.855

Gnomad AMR AF: 0.675

Gnomad ASJ AF: 0.779

Gnomad EAS AF: 0.831

Gnomad SAS AF: 0.915

Gnomad FIN AF: 0.826

Gnomad MID AF: 0.850

Gnomad NFE AF: 0.821

Gnomad OTH AF: 0.781

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.781 AC: 118741 AN: 152072 Hom.: 46675 Cov.: 32 AF XY: 0.782 AC XY: 58174 AN XY: 74344

Gnomad4 AFR AF: 0.719

Gnomad4 AMR AF: 0.675

Gnomad4 ASJ AF: 0.779

Gnomad4 EAS AF: 0.831

Gnomad4 SAS AF: 0.916

Gnomad4 FIN AF: 0.826

Gnomad4 NFE AF: 0.821

Gnomad4 OTH AF: 0.782

Alfa AF: 0.808 Hom.: 24764

Bravo AF: 0.759

Asia WGS AF: 0.845 AC: 2938 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.57
DANN	Benign	0.50

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: rs9510730; hg19: chr13-23994263;