MYO3A

Chr 10ADAR

myosin IIIA

ENSG00000095777 UniProt: Q8NEV4 OMIM: 606808

This actin-dependent motor protein with kinase activity is essential for cochlear hair bundle development and hearing, transporting actin regulatory factors to stereocilia tips and contributing to the characteristic staircase architecture of auditory hair bundles. Mutations cause nonsyndromic hearing loss with both autosomal dominant and autosomal recessive inheritance patterns. The gene shows very low constraint against loss-of-function variants and is highly expressed in the retina and cochlea.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Actin-dependent motor protein with a protein kinase activity, playing an essential role in hearing (PubMed:12032315, PubMed:29880844, PubMed:34788109). Probably also plays a role in vision. Required for normal cochlear hair bundle development and hearing. Plays an important role in the early steps of cochlear hair bundle morphogenesis. Influences the number and lengths of stereocilia to be produced and limits the growth of microvilli within the forming auditory hair bundles thereby contributing to the architecture of the hair bundle, including its staircase pattern. Involved in the elongation of actin in stereocilia tips by transporting the actin regulatory factor ESPN to the plus ends of actin filaments (PubMed:29880844, PubMed:34788109)

OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 1.042 OMIM phenotypes

Clinical Summary— MYO3A

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.04LOEUF

pLI 0.000

Z-score 1.23

OE 0.86 (0.71–1.04)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.13Z-score

OE missense 1.01 (0.96–1.07)

841 obs / 830.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.86 (0.71–1.04)

0≤0.351.4

Missense OE?1.01 (0.96–1.07)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 76 / 88.5Missense obs/exp: 841 / 830.3Syn Z: -0.95

This gene — mechanism propensity

0.7130th %ile

GOF

0.73top 25%

LOF

0.3454th %ile

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

GOFprediction above median

DNprediction above median

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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.