rs137905181

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014363.6(SACS):ā€‹c.9562T>Cā€‹(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: š‘“ 0.00030 ( 0 hom., cov: 33)
Exomes š‘“: 0.00020 ( 1 hom. )

Consequence

SACS
NM_014363.6 missense

Scores

6
10
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 8.87
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
SACSNM_014363.6 linkuse as main transcriptc.9562T>C p.Phe3188Leu missense_variant 10/10 ENST00000382292.9 NP_055178.3 Q9NZJ4-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
SACSENST00000382292.9 linkuse as main transcriptc.9562T>C p.Phe3188Leu missense_variant 10/105 NM_014363.6 ENSP00000371729.3 Q9NZJ4-1

Frequencies

GnomAD3 genomes
AF:
0.000302
AC:
46
AN:
152168
Hom.:
0
Cov.:
33
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:4Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Charlevoix-Saguenay spastic ataxia Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabSep 05, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Likely benign, no assertion criteria providedclinical testingNatera, Inc.Jun 16, 2020- -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsAug 26, 2024- -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicSep 02, 2019- -
Spastic paraplegia Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 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

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

Other links and lift over

dbSNP: rs137905181; hg19: chr13-23908453; API