Bone marrow failure syndrome 4

Summary

Bone marrow failure syndrome 4 (MONDO:0020856) is a disease caused by MYSM1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: MYSM1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 24

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	bone marrow failure syndrome 4
Mondo ID	MONDO:0020856
OMIM	618116
UMLS	C4748257
MedGen	1648485
GARD	0025264
Is cancer (heuristic)	no

Also known as: BMFS4 · BONE MARROW FAILURE SYNDROME 4

Data availability: 24 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › bone marrow disorder › bone marrow failure syndrome › bone marrow failure syndrome 4

Related subtypes (7): autosomal dominant aplasia and myelodysplasia, pancytopenia-developmental delay syndrome, bone marrow failure syndrome 3, bone marrow failure syndrome 6, AMED syndrome, digenic, bone marrow failure syndrome 5, Ziegler-Huang syndrome

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

24 retrieved; paginated sample, class counts are floors:

10 benign, 6 pathogenic, 6 uncertain significance, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1031070	NM_001085487.3(MYSM1):c.1885C>T (p.Gln629Ter)	MYSM1	Pathogenic	criteria provided, multiple submitters, no conflicts
1805964	NM_001085487.3(MYSM1):c.1516C>T (p.Arg506Ter)	MYSM1	Pathogenic	criteria provided, multiple submitters, no conflicts
2501775	NM_001085487.3(MYSM1):c.412C>T (p.Arg138Ter)	MYSM1	Pathogenic	criteria provided, single submitter
561193	NM_001085487.3(MYSM1):c.1168G>T (p.Glu390Ter)	MYSM1	Pathogenic	criteria provided, single submitter
561194	NM_001085487.3(MYSM1):c.1967A>G (p.His656Arg)	MYSM1	Pathogenic	no assertion criteria provided
807637	NM_001085487.3(MYSM1):c.869C>G (p.Ser290Ter)	MYSM1	Pathogenic	criteria provided, single submitter
1514455	NM_001085487.3(MYSM1):c.219-1G>A	MYSM1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2442104	NM_001085487.3(MYSM1):c.1146_1149del (p.Asp382fs)	MYSM1	Likely pathogenic	criteria provided, single submitter
3236453	NM_001085487.3(MYSM1):c.44T>G (p.Val15Gly)	LOC129930616	Uncertain significance	criteria provided, single submitter
1405054	NM_001085487.3(MYSM1):c.1758A>G (p.Ile586Met)	MYSM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1503165	NM_001085487.3(MYSM1):c.1531A>G (p.Asn511Asp)	MYSM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2503517	NM_001085487.3(MYSM1):c.688G>C (p.Asp230His)	MYSM1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3250421	NM_001085487.3(MYSM1):c.2030A>G (p.Gln677Arg)	MYSM1	Uncertain significance	criteria provided, single submitter
4813153	NM_001085487.3(MYSM1):c.1457T>C (p.Val486Ala)	MYSM1	Uncertain significance	criteria provided, single submitter
1164381	NM_001085487.3(MYSM1):c.2031+8A>G	MYSM1	Benign	criteria provided, multiple submitters, no conflicts
1169493	NM_001085487.3(MYSM1):c.2262C>T (p.Leu754=)	MYSM1	Benign	criteria provided, multiple submitters, no conflicts
1169494	NM_001085487.3(MYSM1):c.2165-10G>A	MYSM1	Benign	criteria provided, multiple submitters, no conflicts
1169495	NM_001085487.3(MYSM1):c.69-6T>C	MYSM1	Benign	criteria provided, multiple submitters, no conflicts
1169779	NM_001085487.3(MYSM1):c.2032-8C>A	MYSM1	Benign	criteria provided, multiple submitters, no conflicts
1169780	NM_001085487.3(MYSM1):c.1275A>G (p.Pro425=)	MYSM1	Benign	criteria provided, multiple submitters, no conflicts
1169781	NM_001085487.3(MYSM1):c.790A>G (p.Thr264Ala)	MYSM1	Benign	criteria provided, multiple submitters, no conflicts
1170149	NM_001085487.3(MYSM1):c.400-18C>T	MYSM1	Benign	criteria provided, multiple submitters, no conflicts
1321832	NM_001085487.3(MYSM1):c.1572+22G>C	MYSM1	Benign	criteria provided, multiple submitters, no conflicts
1321833	NM_001085487.3(MYSM1):c.148-29A>G	MYSM1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MYSM1	Definitive	Autosomal recessive	bone marrow failure syndrome 4	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MYSM1	Orphanet:508542	Congenital progressive bone marrow failure-B-cell immunodeficiency-skeletal dysplasia syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYSM1	HGNC:29401	ENSG00000162601	Q5VVJ2	Deubiquitinase MYSM1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MYSM1	Deubiquitinase MYSM1	Metalloprotease with deubiquitinase activity that plays important regulator roles in hematopoietic stem cell function, blood cell production and immune response.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYSM1	Protease	yes		JAMM/MPN+_dom, SANT/Myb, SWIRM

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
cardiac muscle of right atrium	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYSM1	252	ubiquitous	marker	calcaneal tendon, cardiac muscle of right atrium, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYSM1	6,171

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYSM1	Q5VVJ2	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Metalloprotease DUBs	1	300.5×	0.013	MYSM1
Deubiquitination	1	124.1×	0.016	MYSM1
Post-translational protein modification	1	19.2×	0.069	MYSM1
Metabolism of proteins	1	12.4×	0.081	MYSM1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of hair follicle development	1	4213.0×	0.002	MYSM1
regulation of hemopoiesis	1	1532.0×	0.003	MYSM1
pigmentation	1	702.2×	0.004	MYSM1
immune system process	1	391.9×	0.005	MYSM1
regulation of cell migration	1	157.5×	0.010	MYSM1
chromatin remodeling	1	73.0×	0.018	MYSM1
proteolysis	1	34.2×	0.033	MYSM1
positive regulation of transcription by RNA polymerase II	1	14.9×	0.067	MYSM1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYSM1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	MYSM1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MYSM1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.