rs4770433

chr13-23329652-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_014363.6(SACS):c.*484T>C variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.41 in 525,070 control chromosomes in the GnomAD database, including 46,198 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.37 (11482 hom., cov: 32)
  • Exomes 𝑓: 0.43 (34716 hom.)
• Consequence: SACS NM_014363.6 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: 4.44

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BP6: Variant 13-23329652-A-G is Benign according to our data. Variant chr13-23329652-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 311495.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SACS	NM_014363.6	c.*484T>C		3_prime_UTR_variant	10/10	ENST00000382292.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SACS	ENST00000382292.9	c.*484T>C		3_prime_UTR_variant	10/10	5	NM_014363.6	P1

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56412 AN: 151946 Hom.: 11478 Cov.: 32

Gnomad AFR AF: 0.197

Gnomad AMI AF: 0.612

Gnomad AMR AF: 0.418

Gnomad ASJ AF: 0.377

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.398

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.329

Gnomad NFE AF: 0.446

Gnomad OTH AF: 0.374

GnomAD4 exome AF: 0.426 AC: 158810 AN: 373008 Hom.: 34716 Cov.: 0 AF XY: 0.424 AC XY: 82746 AN XY: 195146

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.439

Gnomad4 ASJ exome AF: 0.376

Gnomad4 EAS exome AF: 0.411

Gnomad4 SAS exome AF: 0.392

Gnomad4 FIN exome AF: 0.445

Gnomad4 NFE exome AF: 0.442

Gnomad4 OTH exome AF: 0.418

GnomAD4 genome AF: 0.371 AC: 56424 AN: 152062 Hom.: 11482 Cov.: 32 AF XY: 0.375 AC XY: 27840 AN XY: 74328

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.418

Gnomad4 ASJ AF: 0.377

Gnomad4 EAS AF: 0.395

Gnomad4 SAS AF: 0.398

Gnomad4 FIN AF: 0.463

Gnomad4 NFE AF: 0.446

Gnomad4 OTH AF: 0.377

Alfa AF: 0.428 Hom.: 29947

Bravo AF: 0.359

Asia WGS AF: 0.416 AC: 1446 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive limb-girdle muscular dystrophy type 2C Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Limb-Girdle Muscular Dystrophy, Recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Charlevoix-Saguenay spastic ataxia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
Cadd	Benign	14
Dann	Benign	0.85

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: rs4770433; hg19: chr13-23903791;