rs4770433

Variant names:

• chr13-23329652-A-G
• rs4770433
• NM_014363.6:c.*484T>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong 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, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.44
• Publications: 20 publications found

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 Gene-Disease associations (from GenCC):

• Charlevoix-Saguenay spastic ataxia

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women's Health, Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Benign. The variant received -18 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 VariationId is 311495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.442 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014363.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	NM_014363.6	MANE Select	c.*484T>C		3_prime_UTR	Exon 10 of 10	NP_055178.3
	SACS	NM_001437336.1		c.*484T>C		3_prime_UTR	Exon 11 of 11	NP_001424265.1	A0A804HIQ1
	SACS	NM_001278055.2		c.*484T>C		3_prime_UTR	Exon 8 of 8	NP_001264984.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SACS	ENST00000382292.9	TSL:5 MANE Select	c.*484T>C		3_prime_UTR	Exon 10 of 10	ENSP00000371729.3	Q9NZJ4-1
	SACS	ENST00000455470.6	TSL:1	c.2432-168T>C		intron	N/A	ENSP00000406565.2	H0Y6M8
	SACS	ENST00000682944.1		c.*484T>C		3_prime_UTR	Exon 11 of 11	ENSP00000507173.1	A0A804HIQ1

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

African (AFR) AF: 0.187 AC: 1768 AN: 9444

American (AMR) AF: 0.439 AC: 5052 AN: 11508

Ashkenazi Jewish (ASJ) AF: 0.376 AC: 4547 AN: 12086

East Asian (EAS) AF: 0.411 AC: 11061 AN: 26900

South Asian (SAS) AF: 0.392 AC: 10625 AN: 27122

European-Finnish (FIN) AF: 0.445 AC: 12190 AN: 27402

Middle Eastern (MID) AF: 0.358 AC: 640 AN: 1786

European-Non Finnish (NFE) AF: 0.442 AC: 103488 AN: 234184

Other (OTH) AF: 0.418 AC: 9439 AN: 22576

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

African (AFR) AF: 0.196 AC: 8149 AN: 41530

American (AMR) AF: 0.418 AC: 6388 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.377 AC: 1305 AN: 3466

East Asian (EAS) AF: 0.395 AC: 2046 AN: 5174

South Asian (SAS) AF: 0.398 AC: 1914 AN: 4814

European-Finnish (FIN) AF: 0.463 AC: 4891 AN: 10558

Middle Eastern (MID) AF: 0.330 AC: 97 AN: 294

European-Non Finnish (NFE) AF: 0.446 AC: 30280 AN: 67926

Other (OTH) AF: 0.377 AC: 796 AN: 2112

Alfa AF: 0.418 Hom.: 59321

Bravo AF: 0.359

Asia WGS AF: 0.416 AC: 1446 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal recessive limb-girdle muscular dystrophy type 2C (1)
-	-	1	Charlevoix-Saguenay spastic ataxia (1)
-	-	1	Limb-girdle muscular dystrophy, recessive (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	14
DANN	Benign	0.85
PhyloP100		4.4
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4770433;

hg19: chr13-23903791;