MYH14

Chr 19

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

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 ResearchSummary from RefSeq, OMIM, 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-14 (MYO14). Myosins are actin-dependent motor proteins with diverse functions including regulation of cytokinesis, cell motility, and cell polarity. Mutations in this gene result in one form of autosomal dominant hearing impairment. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.33

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

31 unique Pathogenic / Likely Pathogenic· 819 VUS of 1608 total submissions

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GeneReview available — MYH14

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.24 (0.18–0.33)

0≤0.351.4

Missense OE?0.82 (0.78–0.86)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

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

This gene — mechanism propensity

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

LOF84% 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 hindered1

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

References

1.PMID 31231018 ↗

ClinVar Variant Classifications

1608 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17

Likely Pathogenic14

VUS819

Likely Benign409

Benign185

Conflicting119

Pathogenic

Likely Pathogenic

819

VUS

409

Likely Benign

185

Benign

119

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	15	2	0	0	17
Likely Pathogenic	11	3	0	0	14
VUS	19	726	44	30	819
Likely Benign	1	31	177	200	409
Benign	0	9	152	24	185
Conflicting	—				119
Total	46	771	373	254	1,563

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 23) ClinVar copy-number / structural variants overlap MYH14 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →