MYH9

Chr 22AD

myosin heavy chain 9

Also known as: BDPLT6, DFNA17, EPSTS, FTNS, MATINS, MHA, NMHC-II-A, NMMHC-IIA

NCBI Gene: 4627 ENSG00000100345 UniProt: P35579 OMIM: 160775

The MYH9 gene encodes a non-muscle myosin IIA heavy chain that functions in cytokinesis, cell motility, cytoskeleton reorganization, and maintenance of cell shape. Mutations cause autosomal dominant macrothrombocytopenia with variable features including sensorineural hearing loss, nephritis, and granulocyte inclusions (historically classified as separate syndromes including Fechtner, Sebastian, and Epstein syndromes). This gene is extremely constrained against loss-of-function variants, reflecting its essential cellular functions.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a conventional non-muscle myosin; this protein should not be confused with the unconventional myosin-9a or 9b (MYO9A or MYO9B). The encoded protein is a myosin IIA heavy chain that contains an IQ domain and a myosin head-like domain which is involved in several important functions, including cytokinesis, cell motility and maintenance of cell shape. Defects in this gene have been associated with non-syndromic sensorineural deafness autosomal dominant type 17, Epstein syndrome, Alport syndrome with macrothrombocytopenia, Sebastian syndrome, Fechtner syndrome and macrothrombocytopenia with progressive sensorineural deafness. [provided by RefSeq, Dec 2011]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.092 OMIM phenotypes

Clinical Summary— MYH9

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Gene-Disease Validity (ClinGen)

macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss · 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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ClinVar Variants

69 unique Pathogenic / Likely Pathogenic· 711 VUS of 2021 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MYH9

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.09LOEUF

pLI 1.000

Z-score 9.11

OE 0.04 (0.02–0.09)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.47Z-score

OE missense 0.71 (0.67–0.75)

820 obs / 1151.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.04 (0.02–0.09)

0≤0.351.4

Missense OE?0.71 (0.67–0.75)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 4 / 104.4Missense obs/exp: 820 / 1151.7Syn Z: -3.16

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMYH9-related deafnessOTHERAD

definitiveMYH9-related macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing lossLOFAD

moderateMYH9-related elastin aggregation syndromeOTHERAD

This gene — mechanism propensity

0.5378th %ile

GOF

0.4085th %ile

LOF

0.59top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · 29% of P/LP variants are LoF · LOEUF 0.09

DN1 literature citation

Literature Evidence

DNMYH9-RD mutants phenocopy inhibition, revealing a dominant negative effect.1

LOFAltogether these results indicate that haploinsufficiency of NMMHC-IIA in megakaryocytic lineage is the mechanism of macrothrombocytopenia consequent to MYH9 mutations, whereas in granulocytes a dominant-negative effect of mutant allele is involved in the formation of inclusion bodies.2

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

References

ClinVar Variant Classifications

2021 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23

Likely Pathogenic46

VUS711

Likely Benign728

Benign204

Conflicting256

Pathogenic

Likely Pathogenic

711

VUS

728

Likely Benign

204

Benign

256

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	11	12	0	0	23
Likely Pathogenic	9	36	1	0	46
VUS	16	597	79	19	711
Likely Benign	0	83	308	337	728
Benign	0	19	132	53	204
Conflicting	—				256
Total	36	747	520	409	1,968

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap MYH9 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →