MYH14

Chr 19AD

myosin heavy chain 14

Also known as: DFNA4, DFNA4A, FP17425, MHC16, MYH17, NMHC II-C, NMHC-II-C, PNMHH

NCBI Gene: 79784 ENSG00000105357 UniProt: Q7Z406 OMIM: 608568

This gene encodes a non-muscle myosin that functions as an actin-dependent motor protein involved in cytokinesis, cell shape regulation, and specialized cellular functions including secretion. Mutations cause autosomal dominant deafness (DFNA4A) and a syndrome involving peripheral neuropathy, myopathy, hoarseness, and hearing loss. The gene is highly constrained against loss-of-function variants (LOEUF 0.332), indicating that such variants are likely pathogenic.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismADLOEUF 0.332 OMIM phenotypes

Clinical Summary— MYH14

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ADModerate

Moderate evidence — consider for supplementary testing

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

11 unique Pathogenic / Likely Pathogenic· 237 VUS of 400 total submissions

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GeneReview available — MYH14

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.33LOEUF

pLI 0.042

Z-score 7.46

OE 0.24 (0.18–0.33)

Highly constrained

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

Missense Constraint

2.28Z-score

OE missense 0.82 (0.78–0.86)

1069 obs / 1300.8 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.24 (0.18–0.33)

0≤0.351.4

Missense OE0.82 (0.78–0.86)

0≤0.61.4

Synonymous OE0.90

0≤1.21.6

LoF obs/exp: 27 / 112.3Missense obs/exp: 1069 / 1300.8Syn Z: 1.87

0.79top 25%

GOF

0.6150th %ile

LOF

0.2874th %ile

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

DNprediction above median · 1 literature citation

LOF82% of P/LP variants are LoF · LOEUF 0.33

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

DNFindings: We describe the third family carrying the R941L mutation in MYH14, and demonstrate that the R941L mutation impairs non-muscle myosin protein function. To better understand the molecular basis of the peripheral neuropathy phenotype associated with the R941L mutation, which has been hinderedPMID:31231018

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