rs111540787
Positions:
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3BP4_ModerateBP6BS2
The NM_014363.6(SACS):āc.8339T>Gā(p.Phe2780Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00482 in 1,613,692 control chromosomes in the GnomAD database, including 22 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 0.0033 ( 1 hom., cov: 33)
Exomes š: 0.0050 ( 21 hom. )
Consequence
SACS
NM_014363.6 missense
NM_014363.6 missense
Scores
9
6
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -6 ACMG points.
PP3
?
Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
?
Computational evidence support a benign effect (MetaRNN=0.077881575).
BP6
?
Variant 13-23335537-A-C is Benign according to our data. Variant chr13-23335537-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 240902.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=4, Benign=1}. Variant chr13-23335537-A-C is described in Lovd as [Likely_benign].
BS2
?
High Homozygotes in GnomAdExome4 at 21 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SACS | NM_014363.6 | c.8339T>G | p.Phe2780Cys | missense_variant | 10/10 | ENST00000382292.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SACS | ENST00000382292.9 | c.8339T>G | p.Phe2780Cys | missense_variant | 10/10 | 5 | NM_014363.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00330 AC: 502AN: 152090Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00286 AC: 718AN: 250866Hom.: 3 AF XY: 0.00279 AC XY: 378AN XY: 135614
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GnomAD4 exome AF: 0.00498 AC: 7278AN: 1461484Hom.: 21 Cov.: 37 AF XY: 0.00482 AC XY: 3502AN XY: 727066
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GnomAD4 genome ? AF: 0.00330 AC: 502AN: 152208Hom.: 1 Cov.: 33 AF XY: 0.00281 AC XY: 209AN XY: 74436
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2Benign:3
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 24, 2020 | This variant is associated with the following publications: (PMID: 29482223, 29538656, 23280630, 28535259) - |
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 07, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | SACS: PP3, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 26, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 22, 2015 | - - |
Charlevoix-Saguenay spastic ataxia Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 10, 2020 | - - |
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jun 01, 2020 | - - |
Spastic paraplegia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 13, 2022 | Variant summary: SACS c.8339T>G (p.Phe2780Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0029 in 250866 control chromosomes in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (0.0029 vs 0.0079), allowing no conclusion about variant significance. c.8339T>G has been reported in the literature as segregating in cis with a different putative pathogenic variant (c.12416T>C, p.Leu4139Ser) in a family of five compound heterozygous individuals affected with Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) who harbored c.11675C>G, p.Ser3892* on the other allele (example, Parkinson_2018). The authors cited this variant's frequency and homozygosity in population databases as a rationale for unlikely to be pathogenic. It has also been reported as a non-informative genotype (phase not specified) in at-least one individual sequenced in a cohort of individuals with undiagnosed cerebellar ataxia (example, Coutelier_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay. To our knowledge, no variant specific experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (benign/likely benign, n=4; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign. - |
SACS-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 07, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
1.0
.;D
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at