rs61729954
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP3BP4_StrongBS2
The NM_014363.6(SACS):c.1373C>T(p.Thr458Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00213 in 1,614,206 control chromosomes in the GnomAD database, including 10 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 0.0021 ( 1 hom., cov: 33)
Exomes 𝑓: 0.0021 ( 9 hom. )
Consequence
SACS
NM_014363.6 missense
NM_014363.6 missense
Scores
7
8
4
Clinical Significance
Conservation
PhyloP100: 9.90
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 Benign. Variant got -7 ACMG points.
PP3
Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate [when BayesDel_addAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.009782344).
BS2
High Homozygotes in GnomAdExome4 at 9 AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| SACS | NM_014363.6 | c.1373C>T | p.Thr458Ile | missense_variant | 8/10 | ENST00000382292.9 | NP_055178.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| SACS | ENST00000382292.9 | c.1373C>T | p.Thr458Ile | missense_variant | 8/10 | 5 | NM_014363.6 | ENSP00000371729 | P1 |
Frequencies
GnomAD3 genomes 0.00215 AC: 327AN: 152204Hom.: 1 Cov.: 33
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GnomAD3 exomes AF: 0.00264 AC: 664AN: 251426Hom.: 1 AF XY: 0.00283 AC XY: 384AN XY: 135886
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GnomAD4 exome AF: 0.00213 AC: 3111AN: 1461884Hom.: 9 Cov.: 34 AF XY: 0.00216 AC XY: 1572AN XY: 727246
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GnomAD4 genome 0.00215 AC: 327AN: 152322Hom.: 1 Cov.: 33 AF XY: 0.00193 AC XY: 144AN XY: 74478
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:9Benign:7
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Charlevoix-Saguenay spastic ataxia Uncertain:4Benign:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Thr458Ile was identified in the proband in trans with the SACS p.Leu266Ile variant of uncertain significance. The p.Thr458Ile variant was previously identified in two patients with Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS), and classified as a VUS (Synofzik_2013_PMID:23497566). The variant was observed in homozygous state in a male patient with disease onset at age 30, who had gait disturbance, nystagmus, slight dysmetria, no dysarthria, no pyramidal damage, and urge incontinence. MRI revealed minor atrophy of the superior cerebellar vermis, an arachnoid cyst, and a thinning of the posterior mid-body of the corpus callosum. The p.Thr458Ile variant was also found in compound heterozygous  state (with p.Val995Phe) in a male patient with disease onset at age 20, whose symptoms comprised an early-onset triad of cerebellar ataxia, pyramidal tract signs (bilateral spasticity and extensorplantar response) and peripheral sensorimotor neuropathy. This patient had gait ataxia, cerebellar oculomotor disturbance, dysarthria, dysphagia, intention tremor, dysmetria, and spasiticity (Synofzik_2013_PMID:23497566). The variant was also observed in 14/3500 control chromosomes (heterozygous) (Synofzik_2013_PMID:23497566). The p.Thr458Ile variant was also observed in compound heterozygous state (with a 1.5 Mb macrodeletion), with teenage-onset disease, with severe cerebellar ataxia, mild spasticity, mild peripheral neuropathy, and abnormal fundoscopy (Romano_2012_PMID: 23280630). The p.Thr458Ile variant in compound heterozygous state (in trans with p.Pro2798Gln) in a female patient with multifocal myoclonus (onset 13 years old), tonic clonic seizures (onset 15 years old) as well as additional seizure types, cognitive decline, pyramidal signs, and cerebellar ataxia; the variant was considered likely pathogenic (Nascimento_2016_PMID:27433545). The p.Thr458Ile variant was found in compound heterozygous state (with p.Val995Phe) in a patient with moderate to severe gait ataxia, spasticity, and atrophy of cerebellar vermis with an age of onset before 20 years, and considered pathogenic (Kreuz_2010_Medizinische Genetik 1 Conference Abstracts 2010). The variant was identified in control databases in 720 of 282826 chromosomes (1 homozygous) at a frequency of 0.002546 (Genome Aggregation Database Feb 27, 2017). The variant was identified in dbSNP (rs61729954), ClinVar (Conflicting interpretations of pathogenicity. Uncertain significance [4], benign [2]. The variant was identified in the following populations: Ashkenazi Jewish in 233 of 10370 chromosomes (freq: 0.02247), Other in 32 of 7224 chromosomes (freq: 0.00443), European (non-Finnish) in 352 of 129148 chromosomes (freq: 0.002726), Latino in 55 of 35434 chromosomes (freq: 0.001552), South Asian in 23 of 30612 chromosomes (freq: 0.000751), European (Finnish) in 14 of 25116 chromosomes (freq: 0.000557), African in 11 of 24968 chromosomes (freq: 0.000441), but was not observed in East Asian populations. The p.Thr458 residue is conserved in mammals and other organisms. Computational analyses (SIFT, Polyphen2, MUT Assesor, DANN, MT, FATHMM, MetaLR, Revel) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogencity.  In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
| Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jun 18, 2020 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | May 18, 2021 | - - |
| Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomics England Pilot Project, Genomics England | Jan 23, 2018 | - - |
not provided Uncertain:2Benign:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 13, 2015 | - - |
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 21, 2019 | This variant is associated with the following publications: (PMID: 23497566, 27433545, 23280630, 25401298) - |
| Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Feb 19, 2016 | - - |
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 06, 2019 | - - |
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2024 | SACS: BS1, BS2 - |
Hereditary spastic paraplegia Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 22, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | research | Unit for Genetic & Epidemiological Research on Neurological Disorders, Instituto de Investigação e Inovação em Saúde | Mar 07, 2017 | - - |
SACS-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 05, 2024 | The SACS c.1373C>T variant is predicted to result in the amino acid substitution p.Thr458Ile. This variant was reported in multiple individuals with autosomal recessive hereditary spastic paraplegias (Romano et al 2013. PubMed ID: 23280630; Vural A et al 2021. PubMed ID: 33624863; Muona M et al 2014. PubMed ID: 25401298). This variant is reported in 2.2% of alleles in individuals of Ashkenazi Jewish descent in gnomAD, which may be too common to be disease-causing. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Spastic paraplegia Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | 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 | Feb 25, 2022 | Variant summary: SACS c.1373C>T (p.Thr458Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 282826 control chromosomes, predominantly at a frequency of 0.022 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in SACS causing Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay phenotype (0.0079), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1373C>T has been reported in the literature in individuals affected with Progressive myoclonus epilepsies, Hereditary ataxias and atypical Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay (Muona_2014, Nascimento_2016, Synofzik_2013, Vural_2021). These reports do not provide unequivocal conclusions about association of the variant with Autosomal Recessive Spastic Ataxia Of Charlevoix-Saguenay. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=5), benign (n=2) and likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;.;.
REVEL
Uncertain
Sift
Pathogenic
D;.;.
Sift4G
Pathogenic
D;.;.
Polyphen
D;.;.
Vest4
MVP
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at