rs137905181

Positions:

• chr13-23334314-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014363.6(SACS):​c.9562T>C​(p.Phe3188Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000206 in 1,609,818 control chromosomes in the GnomAD database, including 1 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 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: SACS NM_014363.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 8.87

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21307245).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SACS	NM_014363.6	c.9562T>C	p.Phe3188Leu	missense_variant	10/10	ENST00000382292.9	NP_055178.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SACS	ENST00000382292.9	c.9562T>C	p.Phe3188Leu	missense_variant	10/10	5	NM_014363.6	ENSP00000371729.3

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152168 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00210

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000283 AC: 70 AN: 247244 Hom.: 1 AF XY: 0.000209 AC XY: 28 AN XY: 133950

Gnomad AFR exome AF: 0.0000637

Gnomad AMR exome AF: 0.000497

Gnomad ASJ exome AF: 0.000802

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000340

Gnomad OTH exome AF: 0.000999

GnomAD4 exome AF: 0.000196 AC: 286 AN: 1457532 Hom.: 1 Cov.: 37 AF XY: 0.000178 AC XY: 129 AN XY: 724772

Gnomad4 AFR exome AF: 0.0000301

Gnomad4 AMR exome AF: 0.000630

Gnomad4 ASJ exome AF: 0.000652

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000202

Gnomad4 OTH exome AF: 0.000266

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152286 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74470

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00209

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000284 Hom.: 0

Bravo AF: 0.000472

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000231 AC: 28

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jun 16, 2020	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 26, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 02, 2019	- -

Spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.46
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	.;D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Uncertain	0.46	D
MutationAssessor	Benign	1.1	.;L
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.9	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.021	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.98	.;D
Vest4		0.95
MutPred		0.54		.;Gain of catalytic residue at N3190 (P = 0.003);
MVP		0.92
ClinPred		0.15	T
GERP RS		5.5
Varity_R		0.72
gMVP		0.79

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: rs137905181; hg19: chr13-23908453;