MYSM1
protein-codingMyb like, SWIRM and MPN domains 1, the group of Myb/SANT domain containing|JAMM/MPN+ metallopeptidase family
Gene summary
Enables deubiquitinase activity; histone binding activity; and transcription coactivator activity. Involved in chromatin remodeling; positive regulation of transcription by RNA polymerase II; and regulation of hemopoiesis. Located in nucleolus and nucleoplasm. Part of protein-containing complex. Implicated in diabetic retinopathy. [provided by Alliance of Genome Resources, Jul 2025]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~56.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0020856
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0020856
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0020856
Submitter: ClinGen
MYSM1 was first reported in relation to autosomal recessive bone marrow syndrome in 2013 (Alsultan et al., PMID: 24288411). Bone marrow failure due to MYSM1 deficiency is characterized by anemia, leukopenia, thrombocytopenia, and B cell deficiency resulting in recurrent infections and in some cases, non hematologic features such as dysmorphic features, skeletal abnormalities, and developmental delay. At least seven variants (e.g. missense, nonsense, frameshift, and canonical splice) that have been reported in seven probands in seven publications (PMIDs: 24288411, 28115216, 26220525, 33858043, 30735661, 32640305, 35295078) are included in this curation. MYSM1 variants segregated with disease in two families and heterozygous carriers were asymptomatic (PMIDs: 28115216, 24288411). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by mouse models, in vivo genetic reversion in an affected patient, biochemical function, functional alteration, and protein interactions studies. (PMIDs: 26125289, 26474655, 22184403, 26220525, 28115216). In summary, there is definitive evidence supporting the relationship between MYSM1 and autosomal recessive bone marrow failure. 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 SCID-CID GCEP on June 7, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0020856
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Craniofacial; Dental; Dermatologic; Hematologic; Neurologic; Ophthalmologic
Intervention: Allergy/Immunology/Infectious
Rationale: The condition can involve anemia and increased risk of infection, and interventions such as RBC transfusions and early and aggressive treatment of infections may be beneficial; BMT has been described
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MYSM1 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001085487.3. 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 | 6 | 119 | 2 | 127 | ||
| missense | 1 | 215 | 15 | 4 | 235 | |
| nonsense | 18 | 2 | 20 | |||
| start loss | 1 | 1 | ||||
| frameshift | 8 | 3 | 1 | 12 | ||
| splice donor/acceptor (+/-2bp) | 6 | 4 | 10 | |||
| Total | 27 | 9 | 229 | 134 | 6 | 405 |
Highest pathogenic variant AF is 0.00020214781
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001078956.1 | 20 | MANE Select | |
| Ensembl | ENSP00000418734.1 | 20 | MANE Select | |
| Ensembl | ENSP00000499373.1 | 20 | Standard | |
| Ensembl | ENSP00000499373.1 | 20 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| mysm1 | Danio rerio | Structure: pharyngeal arch cartilage Quality: malformed abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Post-translational protein modification
- Metabolism of proteins
- Metalloprotease DUBs
- Deubiquitination
Biological Process
- chromatin remodeling
- regulation of cell migration
- monoubiquitinated histone H2A deubiquitination
- pigmentation
- positive regulation of transcription by RNA polymerase II
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA binding
- transcription coactivator activity
- thiol-dependent ubiquitin-specific protease activity
- metallopeptidase activity
Cellular Component
- nucleus
- nucleoplasm
- plasma membrane
- protein-containing complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000472487
- Coding exons
- 20
- Length
- 45354
- Individuals with no LoFs
- 124737
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 57
- Defined
- 124794
- p
- 0.000228
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.22 | 353 | 424 | 0.833 | 0.0000213 | 5478 |
| Missense (PolyPhen) | 86 | 132.92 | 0.647 | 1632 | ||
| Synonymous | 0.439 | 132 | 139 | 0.953 | 0.00000664 | 1430 |
| Loss of Function | 4.90 | 13 | 50.6 | 0.257 | 0.00000267 | 632 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00027 | 0.00026 | rare |
| Latino/Admixed American | 0.00019 | 0.00017 | rare |
| Ashkenazi Jewish | 0.00021 | 0.00020 | rare |
| East Asian | 0.00017 | 0.00017 | rare |
| Finnish | 0.000094 | 0.000093 | rare |
| European (Non-Finnish) | 0.00036 | 0.00034 | rare |
| South Asian | 0.000033 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Metalloprotease that specifically deubiquitinates monoubiquitinated histone H2A, a specific tag for epigenetic transcriptional repression, thereby acting as a coactivator. Preferentially deubiquitinates monoubiquitinated H2A in hyperacetylated nucleosomes. Deubiquitination of histone H2A leads to facilitate the phosphorylation and dissociation of histone H1 from the nucleosome. Acts as a coactivator by participating in the initiation and elongation steps of androgen receptor (AR)-induced gene activation. {ECO:0000269|PubMed:17707232}.;
Intolerance Scores
- LoFtool
- 0.748
- RVIS EVS
- 0.16
- RVIS percentile EVS
- 64.82
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.530
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |