dbSNP rs4770433: SACS:c.*484T>C (chr13-23329652-A-G) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.44

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SACS	NM_014363.6 link	c.*484T>C		3_prime_UTR_variant	Exon 10 of 10	ENST00000382292.9	NP_055178.3	Q9NZJ4-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292 link	c.*484T>C		3_prime_UTR_variant	Exon 10 of 10	5	NM_014363.6	ENSP00000371729.3		Q9NZJ4-1

Frequencies

GnomAD3 genomes

AF:

0.371

AC:

56412

AN:

151946

Hom.:

11478

Cov.:

show subpopulations

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.:

AF XY:

0.424

AC XY:

82746

AN XY:

195146

show subpopulations

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.:

AF XY:

0.375

AC XY:

27840

AN XY:

74328

show subpopulations

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:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Limb-girdle muscular dystrophy, recessive

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive limb-girdle muscular dystrophy type 2C

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Charlevoix-Saguenay spastic ataxia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.27

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over