MYH10

Chr 17

myosin heavy chain 10

Also known as: NMMHC-IIB, NMMHCB

NCBI Gene: 4628 ENSG00000133026 UniProt: P35580 OMIM: 160776

This protein is a cellular myosin that functions in cytokinesis, cell shape maintenance, and cytoskeletal reorganization during cell spreading. Mutations cause autosomal dominant May-Hegglin anomaly and related macrothrombocytopenia syndromes characterized by bleeding disorders due to large platelets and low platelet counts. The gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be severe.

OMIM ResearchSummary from UniProt

This gene encodes a member of the myosin superfamily. The protein represents a conventional non-muscle myosin; it should not be confused with the unconventional myosin-10 (MYO10). Myosins are actin-dependent motor proteins with diverse functions including regulation of cytokinesis, cell motility, and cell polarity. Mutations in this gene have been associated with May-Hegglin anomaly and developmental defects in brain and heart. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.17

Clinical Summary— MYH10

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder with or without congenital anomalies · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.17LOEUF

pLI 1.000

Z-score 8.96

OE 0.10 (0.07–0.17)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

5.01Z-score

OE missense 0.58 (0.55–0.62)

671 obs / 1148.4 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.10 (0.07–0.17)

0≤0.351.4

Missense OE?0.58 (0.55–0.62)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 12 / 116.2Missense obs/exp: 671 / 1148.4Syn Z: 1.19

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateMYH10-related multiple congenital anomaliesDNAD

This gene — mechanism propensity

0.5967th %ile

GOF

0.4283th %ile

LOF

0.57top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.17

DN1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNMYH10 variant overexpression produced a dominant-negative effect on ciliary length.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References