MYO15A

protein-coding

myosin XVA, the group of FERM domain containing|Myosin heavy chains, class XV

Gene summary

This gene encodes an unconventional myosin. This protein differs from other myosins in that it has a long N-terminal extension preceding the conserved motor domain. Studies in mice suggest that this protein is necessary for actin organization in the hair cells of the cochlea. Mutations in this gene have been associated with profound, congenital, neurosensory, nonsyndromal deafness. This gene is located within the Smith-Magenis syndrome region on chromosome 17. Read-through transcripts containing an upstream gene and this gene have been identified, but they are not thought to encode a fusion protein. Several alternatively spliced transcript variants have been described, but their full length sequences have not been determined. [provided by RefSeq, Jul 2008]

Previous symbols:

DFNB3
MYO15

MANE transcript

NM_016239.4

Inheritance

ClinVar variants

P:763U:988B:1272

Top phenotype

Deafness, autosomal recessive 3

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr17:18,108,756-18,179,802

External References & Databases

Ensembl (ENSG00000091536)

Transcript & Mutation Effects

hg38 • Region Span ~71.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive nonsyndromic hearing loss 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010860

Submitter: Labcorp Genetics (formerly Invitae)

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

The MYO15A gene has been associated with autosomal recessive nonsyndromic hearing loss using the ClinGen Clinical Validity Framework as of 10/6/17. This association was made using case-level data. Twelve variants (missense, nonsense, frameshift and splice-site) were scored for this curation. MYO15A was first associated with this disease in humans as early as 1998 (Wang et al.). Association is seen in at least 12 probands in 4 publications (27375115, 26226137, 23208854, 19309289), however much more evidence is available in the literature. The maximum score for genetic evidence and experimental evidence has been reached. Rehman et al. 2016 provides a summary of available published MYO15A variants (27375115). This gene-disease association is supported by two mouse models and a mouse rescue (9603735, 10915760). In summary, MYO15A is definitively associated with autosomal recessive nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 11/21/17.

autosomal recessive nonsyndromic hearing loss 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0010860

Submitter: PanelApp Australia

autosomal recessive nonsyndromic hearing loss 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010860

Submitter: G2P

Clinical Genomic Database (CGD)

Deafness, autosomal recessive 3AR

Manifestation: Audiologic/Otolaryngologic

Intervention: Audiologic/Otolaryngologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development

Refs: 17851452; 23226338

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to MYO15A variants in ClinVar

20 Conditions Cataloged

not providedTotal: 2840

Autosomal recessive nonsyndromic hearing loss 3Total: 862

Inborn genetic diseasesTotal: 596

not specifiedTotal: 364

MYO15A-related disorderTotal: 97

Rare genetic deafnessTotal: 50

Hearing impairmentTotal: 27

Nonsyndromic genetic hearing lossTotal: 17

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016239.4. 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	2 clinvar	4 clinvar	23 clinvar	1041 clinvar	7 clinvar	1077
missense	23 clinvar	142 clinvar	959 clinvar	216 clinvar	6 clinvar	1346
nonsense	108 clinvar	47 clinvar	1 clinvar	1 clinvar		157
start loss						0
frameshift	200 clinvar	104 clinvar	1 clinvar			305
splice donor/acceptor (+/-2bp)	53 clinvar	80 clinvar	4 clinvar	1 clinvar		138
Total	386	377	988	1259	13	3023

Highest pathogenic variant AF is 0.00019952585

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016239.4	RefSeq	NP_057323.3	65	MANE Select
ENST00000647165.2	Ensembl	ENSP00000495481.1	65	MANE Select
ENST00000418233.7	Ensembl	ENSP00000408800.3	22	Standard
ENST00000556535.5	Ensembl	ENSP00000451782.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

sensory perception of sound
locomotory behavior
inner ear morphogenesis

Molecular Function

motor activity
actin binding
calmodulin binding
ATP binding

Cellular Component

cytoplasm
myosin complex
stereocilium
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000205890
Coding exons: 65
Length: 71097
Individuals with no LoFs: 124453
Homozygous LoFs: 1
Heterozygous LoFs: 468
Defined: 124922
p: 0.00188

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.646	1975	2.06e+3	0.960	0.000147	22488
Missense (PolyPhen)		138	152.41	0.90545		1301
Synonymous	1.60	826	886	0.932	0.0000662	7280
Loss of Function	3.78	116	169	0.686	0.00000936	1848

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.0025	0.0025	notable
Ashkenazi Jewish	0.00060	0.00060	rare
East Asian	0.0040	0.0038	notable
Finnish	0.00056	0.00056	rare
European (Non-Finnish)	0.0019	0.0018	notable
South Asian	0.0022	0.0019	notable
Other	0.0022	0.0021	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Their highly divergent tails are presumed to bind to membranous compartments, which would be moved relative to actin filaments. Required for the arrangement of stereocilia in mature hair bundles (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.160

Intolerance Scores

LoFtool: 0.0478
RVIS EVS: -1.26
RVIS percentile EVS: 5.35

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.620

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High