SNUPN
protein-codingsnurportin 1
Gene summary
The nuclear import of the spliceosomal snRNPs U1, U2, U4 and U5, is dependent on the presence of a complex nuclear localization signal. The latter is composed of the 5'-2,2,7-terminal trimethylguanosine (m3G) cap structure of the U snRNA and the Sm core domain. The protein encoded by this gene interacts specifically with m3G-cap and functions as an snRNP-specific nuclear import receptor. Alternatively spliced transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]
- RNUT1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~28.4 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0971171
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0971171
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0100584
Submitter: ClinGen
SNUPN encodes Snurportin 1, a nuclear import receptor essential for transporting small nuclear ribonucleoproteins into the nucleus, which are crucial for RNA splicing. SNUPN was first reported in relation to autosomal recessive limb-girdle muscular dystrophy in 2024 (Nashabat et al., PMID: 38413582). Among the 21 patients from 16 families described to date, symptom onset ranges from birth to 10 years, with progressive muscle weakness predominantly affecting proximal muscles, elevated serum creatine kinase levels, and skeletal muscle biopsies showing type I fibre predominance, hypertrophy, and fibrosis. Central nervous system involvement is variable and may include developmental delay and cerebellar atrophy. Joint contracutres, scoliosis, and ocular features like congenital bilateral cataracts may also occur, and respiratory insufficiency is common. Given the spectrum of patient phenotypes, the disease entity was defined as SNUPN-related muscular dystrophy with or without multi-system involvement. Nine variants (4 nonsense, 2 missense, 2 frameshift, 1 splice site) reported in 21 probands from two publications (PMID: 38413582, 38366623) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence, including decreased SNUPN expression in patient fibroblasts, impaired protein-protein interaction in mutant HEK293T and HeLa cells, and aberrant RNA splicing affecting extracellular matrix components in patient fibroblasts and muscle tissue. Additionally, a muscle-specific Snup knockdown Drosophila model demonstrated age-dependent reduction in climbing activity and impaired survival (PMID: 38413582, 38366623). In summary, there is strong evidence supporting the relationship between SNUPN and autosomal recessive SNUPN-related muscular dystrophy with or without multi-system involvement. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. Of note, SNUPN has also been implicated in spinocerebellar atrophy in a preprint (Okubo et al., MedRxiv: 2024.07.11.24310169) in 2024. This will be assessed during re-evaluation or when further evidence become available. This classification was approved by the ClinGen Muscular Dystrophies and Myopathies GCEP on October 8, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0971171
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: 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 SNUPN variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_005701.4. 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 | 1 | 1 | ||||
| missense | 3 | 49 | 3 | 55 | ||
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 1 | 1 | 2 | |||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 1 | 5 | 51 | 3 | 0 | 60 |
Highest pathogenic variant AF is 0.00016170103
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_005692.1 | 8 | MANE Select | |
| Ensembl | ENSP00000309831.5 | 8 | MANE Select | |
| RefSeq | NP_001036046.1 | 8 | Standard | |
| RefSeq | NP_001036053.1 | 8 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- RNA transport - Homo sapiens (human)
- snRNP Assembly
- Metabolism of RNA
- Metabolism of non-coding RNA
Biological Process
- spliceosomal snRNP assembly
- protein import into nucleus
- import into nucleus
- snRNA import into nucleus
Molecular Function
- RNA cap binding
- protein binding
- nuclear import signal receptor activity
Cellular Component
- nuclear pore
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000564644
- Coding exons
- 8
- Length
- 28387
- Individuals with no LoFs
- 125659
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 88
- Defined
- 125747
- p
- 0.000350
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.608 | 175 | 199 | 0.879 | 0.0000104 | 2368 |
| Missense (PolyPhen) | 54 | 56.579 | 0.95442 | 634 | ||
| Synonymous | 1.09 | 63 | 75.0 | 0.840 | 0.00000393 | 661 |
| Loss of Function | -0.157 | 21 | 20.2 | 1.04 | 0.00000110 | 226 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.00041 | 0.00040 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00027 | 0.00027 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00043 | 0.00043 | rare |
| South Asian | 0.00056 | 0.00056 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Functions as an U snRNP-specific nuclear import adapter. Involved in the trimethylguanosine (m3G)-cap-dependent nuclear import of U snRNPs. Binds specifically to the terminal m3G-cap U snRNAs. {ECO:0000269|PubMed:10209022, ECO:0000269|PubMed:15920472, ECO:0000269|PubMed:16030253, ECO:0000269|PubMed:9670026}.;
Intolerance Scores
- LoFtool
- 0.518
- RVIS EVS
- 0.6
- RVIS percentile EVS
- 82.66
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.990
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |