MYSM1

Chr 1AR

Myb like, SWIRM and MPN domains 1

Also known as: 2A-DUB, 2ADUB, BMFS4

NCBI Gene: 114803 ENSG00000162601 UniProt: Q5VVJ2 OMIM: 612176

Encodes a metalloprotease with deubiquitinase activity that regulates hematopoietic stem cell function, blood cell production, and immune responses by removing ubiquitin chains from key signaling proteins and deubiquitinating histone H2A to control gene transcription. Mutations cause bone marrow failure syndrome 4, an autosomal recessive disorder affecting blood cell production. The gene is highly constrained against loss-of-function variants (LOEUF 0.408), reflecting its critical role in hematopoiesis.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.411 OMIM phenotype

Clinical Summary— MYSM1

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Gene-Disease Validity (ClinGen)

bone marrow failure syndrome 4 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.26) despite low pLI — interpret in context.

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ClinVar Variants

35 unique Pathogenic / Likely Pathogenic· 230 VUS of 563 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.043

Z-score 4.90

OE 0.26 (0.17–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.22Z-score

OE missense 0.83 (0.76–0.91)

353 obs / 423.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.26 (0.17–0.41)

0≤0.351.4

Missense OE?0.83 (0.76–0.91)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 13 / 50.6Missense obs/exp: 353 / 423.6Syn Z: 0.44

ClinVar Variant Classifications

563 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27

Likely Pathogenic8

VUS230

Likely Benign235

Benign32

Conflicting9

Pathogenic

Likely Pathogenic

230

VUS

235

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	25	1	1	0	27
Likely Pathogenic	8	0	0	0	8
VUS	2	214	10	4	230
Likely Benign	0	6	114	115	235
Benign	0	7	21	4	32
Conflicting	—				9
Total	35	228	146	123	541

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

11 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap MYSM1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →