MYH9

Chr 22

myosin heavy chain 9

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

NCBI Gene: 4627 ENSG00000100345 UniProt: P35579

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 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 ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtMacrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss

UniProtDeafness, autosomal dominant, 17

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss · AD · ClinGen 2018

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

208

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.09

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — MYH9

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in MYH9?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 31

1,968 rare PASS variants

Rare truncating (LoF)

1 in 3,500

73 rare PASS variants

Rare synonymous (reference)

1 in 32

1,108 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MYH9. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 39	1 in 4,100
South Asian	~43k	1 in 30	1 in 2,000
Remaining (unassigned)	~30k	1 in 32	1 in 5,200
European (Finnish)	~27k	1 in 61	1 in 4,200
Admixed American	~22k	1 in 30	1 in 3,700
African / African American	~21k	1 in 26	1 in 3,100
East Asian	~20k	1 in 32	1 in 3,300
Ashkenazi Jewish	~13k	1 in 160	1 in 1,500
Middle Eastern	~2,884	1 in 31	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 40 coding exons well covered in gnomAD exomes and genomes.? see exons ↓