MYH14

protein-coding

myosin heavy chain 14, the group of Myosin heavy chains, class II

Gene summary

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]

Previous symbols:

DFNA4

MANE transcript

NM_001145809.2

Inheritance

ClinVar variants

P:42U:861B:376

Top phenotype

Deafness, autosomal dominant 4A; Deafness, autosomal dominant 4B; Peripheral neuropathy, myopathy, hoarseness, and hearing loss

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr19:50,188,186-50,310,542

External References & Databases

Ensembl (ENSG00000105357)

Transcript & Mutation Effects

hg38 • Region Span ~122.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant nonsyndromic hearing loss 4ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010915

Submitter: Labcorp Genetics (formerly Invitae)

peripheral neuropathy-myopathy-hoarseness-hearing loss syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013711

Submitter: Labcorp Genetics (formerly Invitae)

peripheral neuropathy-myopathy-hoarseness-hearing loss syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013711

Submitter: Orphanet

peripheral neuropathy-myopathy-hoarseness-hearing loss syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013711

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 4ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010915

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

nonsyndromic genetic hearing lossMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

The relationship between MYH14 and autosomal dominant nonsyndromic genetic deafness was described in 2004 by Donaudy et al. (PMID:15015131). At least 14 unique variants (missense, nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. MYH14 is thought to play a beneficial role in the protection of the cochlea after acoustic over-stimulation and that loss of function leads to progressive hearing loss (PMID: 28101381). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Hearing Loss Working Group on 8/31/2020. Of note, MYH14 has also been associated with a neuropathy phenotype that includes hearing loss, but that evidence was not included in this curation.

autosomal dominant nonsyndromic hearing loss 4ADEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010915

Submitter: Ambry Genetics

peripheral neuropathy-myopathy-hoarseness-hearing loss syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0013711

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 4A; Deafness, autosomal dominant 4B; Peripheral neuropathy, myopathy, hoarseness, and hearing lossAD

Manifestation: Audiologic/Otolaryngologic; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: The onset of deafness has been described as postlingual

Refs: 7655461; 11938438; 15015131; 16222661; 21480433; 21368133

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYH14 variants in ClinVar

22 Conditions Cataloged

not providedTotal: 1116

not specifiedTotal: 345

Inborn genetic diseasesTotal: 291

Autosomal dominant nonsyndromic hearing loss 4ATotal: 226

MYH14-related disorderTotal: 196

Peripheral neuropathy-myopathy-hoarseness-hearing loss syndromeTotal: 58

Hearing impairmentTotal: 8

Meniere diseaseTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001145809.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			31 clinvar	251 clinvar	14 clinvar	296
missense	2 clinvar	11 clinvar	791 clinvar	99 clinvar	11 clinvar	914
nonsense	6 clinvar	1 clinvar	7 clinvar			14
start loss			1 clinvar			1
frameshift	9 clinvar	6 clinvar	9 clinvar	1 clinvar		25
splice donor/acceptor (+/-2bp)		7 clinvar	22 clinvar			29
Total	17	25	861	351	25	1279

Highest pathogenic variant AF is 0.00003592461

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001145809.2	RefSeq	NP_001139281.1	42	MANE Select
ENST00000642316.2	Ensembl	ENSP00000493594.1	42	MANE Select
NM_001077186.2	RefSeq	NP_001070654.1	41	Standard
NM_024729.4	RefSeq	NP_079005.3	40	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Salmonella infection - Homo sapiens (human)
Tight junction - Homo sapiens (human)
Regulation of actin cytoskeleton - Homo sapiens (human)
Developmental Biology
Signal Transduction

Biological Process

skeletal muscle contraction
skeletal muscle tissue development
sensory perception of sound
regulation of cell shape
neuronal action potential

Molecular Function

microfilament motor activity
calmodulin binding
ATP binding
ATPase activity
actin-dependent ATPase activity

Cellular Component

stress fiber
cytosol
brush border
membrane
myosin II complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000601313
Coding exons: 42
Length: 122360
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 33
Defined: 125747
p: 0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.28	1069	1.30e+3	0.822	0.0000951	12845
Missense (PolyPhen)		381	501.56	0.75963		4787
Synonymous	1.87	476	531	0.897	0.0000352	4160
Loss of Function	7.46	27	112	0.241	0.00000620	1204

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00031	0.00030	rare
East Asian	0.00017	0.00016	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00018	0.00018	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping. {ECO:0000250}.;
Disease: DISEASE: Deafness, autosomal dominant, 4A (DFNA4A) [MIM:600652]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:15015131, ECO:0000269|PubMed:16222661}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Peripheral neuropathy, myopathy, hoarseness, and hearing loss (PNMHH) [MIM:614369]: A complex phenotype of progressive peripheral neuropathy and distal myopathy, with later onset of hoarseness and hearing loss. Affected individuals develop distal muscle weakness at a mean age of 10.6 years, followed by progressive atrophy of these muscles. The lower limbs are more severely affected than the upper limbs, and the muscle weakness first affects anterior leg muscles and later posterior leg muscles. {ECO:0000269|PubMed:21480433}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.145

Intolerance Scores

LoFtool: 0.0292
RVIS EVS: -2.24
RVIS percentile EVS: 1.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.428

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium