SIL1
protein-codingSIL1 nucleotide exchange factor, the group of Armadillo like helical domain containing
Gene summary
This gene encodes a resident endoplasmic reticulum (ER), N-linked glycoprotein with an N-terminal ER targeting sequence, 2 putative N-glycosylation sites, and a C-terminal ER retention signal. This protein functions as a nucleotide exchange factor for another unfolded protein response protein. Mutations in this gene have been associated with Marinesco-Sjogren syndrome. Alternate transcriptional splice variants have been characterized. [provided by RefSeq, Jul 2008]
- MSS
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~346.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009567
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009567
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0009567
Submitter: ClinGen
SIL1 was first reported in relation to the autosomal recessive disorder Marinesco-Sjogren syndrome (MSS) in 2005 (Senderek et al, PMID: 16282977; Anttonen et al, PMID: 16282978). MSS is a multisystem disorder that is characterized by cerebellar dysfunction and ataxia, early-onset bilateral cataracts, developmental delays, intellectual disability, skeletal deformities, short stature and progressive myopathy (Anttonen, 2019, PMID: 20301371; Chiesa and Sallese, 2020, PMID: 31701543; Ichhaporia and Hendershot, 2021, PMID: 33557244). MSS is the only disorder known to be caused by variants in SIL1. SIL1 encodes an adenine nucleotide exchange factor for the ER homologue of Hsp (heat shock protein) 70 family, also known as BiP, HSPA5, or GRP78. Recent reviews discuss the role of SIL1 in the ER, and indicate that lack of SIL1 results in accumulation of unfolded proteins within the ER, providing a pathogenic mechanism for the features of MSS (Chiesa and Sallese, 2020, PMID: 31701543; Ichhaporia and Hendershot, 2021, PMID: 33557244). Over 40 MSS-associated variants have been reported in SIL1, including nonsense, frameshift, splice site inframe deletions, and missense variants (Ichhaporia and Hendershot, 2021, PMID: 33557244). Of note, about 40% of individuals with characteristic features of MSS do not have identifiable variants in SIL1 (Krieger et al, 2013, PMID: 24176978). Other causes have not yet been identified. Thirteen variants that have been reported in eleven probands in three publications are included in this curation (Senderek et al, 2005, PMID: 16282977; Anttonen et al, 2005, PMID: 16282978; Krieger et al, 2013, PMID: 24176978). In addition, linkage data is included from Finnish families in which affected individuals are homozygous for a founder variant in the Finnish population (Anttonen et al, 2005, PMID: 16282978). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence including a spontaneous mouse model known as the woozy mouse (Zhao et al, 2005, PMID: 16116427; Kayashi et al, 2018, PMID: 28723727) and a knock out mouse model (Zhao et al, 2005, PMID: 16116427) both of which recapitulate the cortical atrophy, ataxia, and myopathy observed in human patients, but which typically do not develop cataracts. In addition, cortical neuron migration defects in mice resulting from Sil1 RNAi knockdown were rescued by human SIL1 (Inaguma et al, 2014, PMID: 24473200). In addition, results from analysis of cells and tissues from individuals with MSS and animal models of MSS is reviewed in detail in PMID: 31701543 (Table 2) and PMID: 33557244. In summary, there is definitive evidence supporting the relationship between SIL1 and the autosomal recessive disorder Marinesco-Sjogren syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Lysosomal Diseases Gene Curation Expert Panel on December 5, 2023 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0009567
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009567
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Endocrine; Musculoskeletal; Neurologic; Ophthalmologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SIL1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_022464.5. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 7 | 107 | 1 | 115 | ||
| missense | 2 | 167 | 14 | 2 | 185 | |
| nonsense | 4 | 4 | 8 | |||
| start loss | 2 | 2 | ||||
| frameshift | 14 | 3 | 17 | |||
| splice donor/acceptor (+/-2bp) | 5 | 5 | 7 | 17 | ||
| Total | 25 | 12 | 183 | 121 | 3 | 344 |
Highest pathogenic variant AF is 0.00006139565
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_071909.1 | 9 | MANE Select | |
| Ensembl | ENSP00000378294.2 | 9 | MANE Select | |
| RefSeq | NP_001032722.1 | 9 | Standard | |
| Ensembl | ENSP00000265195.5 | 9 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| sil1 | Danio rerio | Structure: Purkinje cell Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Protein processing in endoplasmic reticulum - Homo sapiens (human)
Biological Process
- protein folding
- intracellular protein transport
- regulation of catalytic activity
Molecular Function
- adenyl-nucleotide exchange factor activity
- protein binding
- unfolded protein binding
Cellular Component
- extracellular space
- cytoplasm
- endoplasmic reticulum
- endoplasmic reticulum lumen
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000394817
- Coding exons
- 9
- Length
- 346838
- Individuals with no LoFs
- 125680
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 68
- Defined
- 125748
- p
- 0.000270
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.471 | 234 | 255 | 0.917 | 0.0000158 | 2986 |
| Missense (PolyPhen) | 89 | 95.05 | 0.93635 | 1120 | ||
| Synonymous | -0.636 | 127 | 118 | 1.07 | 0.00000793 | 934 |
| Loss of Function | 2.79 | 7 | 20.7 | 0.338 | 9.89e-7 | 240 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00012 | 0.00012 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.000055 | 0.000054 | rare |
| Finnish | 0.00084 | 0.00083 | rare |
| European (Non-Finnish) | 0.00033 | 0.00032 | rare |
| South Asian | 0.00013 | 0.00013 | rare |
| Other | 0.00086 | 0.00081 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Required for protein translocation and folding in the endoplasmic reticulum (ER). Functions as a nucleotide exchange factor for the ER lumenal chaperone HSPA5. {ECO:0000269|PubMed:12356756}.;
- Disease
- DISEASE: Marinesco-Sjoegren syndrome (MSS) [MIM:248800]: Autosomal recessive multisystem disorder which is characterized by cerebellar ataxia due to cerebellar atrophy, with Purkinje and granule cell loss and myopathy featuring marked muscle replacement with fat and connective tissue. Other cardinal features include bilateral cataracts, hypergonadotrophic hypogonadism and mild to severe mental retardation. Skeletal abnormalities, short stature, dysarthria, strabismus and nystagmus are also frequent findings. Mutational inactivation of this protein may result in ER stress- induced cell death signaling or malfunctioning chaperone machineries that mishandle client proteins which are critical for the organs targeted in MSS. {ECO:0000269|PubMed:16282977, ECO:0000269|PubMed:16282978}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.503
Intolerance Scores
- LoFtool
- 0.747
- RVIS EVS
- 0.42
- RVIS percentile EVS
- 77.23
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.344
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |