POU4F3

Summary

POU4F3 (POU class 4 homeobox 3, HGNC:9220) is a protein-coding gene on chromosome 5q32, encoding POU domain, class 4, transcription factor 3 (Q15319). Acts as a transcriptional activator. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a member of the POU-domain family of transcription factors. POU-domain proteins have been observed to play important roles in control of cell identity in several systems. This protein is found in the retina and may play a role in determining or maintaining the identities of a small subset of visual system neurons. Defects in this gene are the cause of non-syndromic sensorineural deafness autosomal dominant type 15.

Source: NCBI Gene 5459 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 182 total — 10 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 2
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002700

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9220
Approved symbol	POU4F3
Name	POU class 4 homeobox 3
Location	5q32
Locus type	gene with protein product
Status	Approved
Aliases	BRN3C
Ensembl gene	ENSG00000091010
Ensembl biotype	protein_coding
OMIM	602460
Entrez	5459

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000646991, ENST00000914229

RefSeq mRNA: 1 — MANE Select: NM_002700 NM_002700

CCDS: CCDS4281

Canonical transcript exons

ENST00000646991 — 2 exons

Exon	Start	End
ENSE00000766800	146339548	146341728
ENSE00003830151	146338839	146339232

Expression profiles

Bgee: expression breadth tissue_specific, 6 present calls, max score 61.60.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6680 / max 738.4095, expressed in 17 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
59215	0.5328	9
59216	0.1352	7

Top tissues by expression

213 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	61.60	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
medial globus pallidus	UBERON:0002477	48.63	gold quality
buccal mucosa cell	CL:0002336	47.54	gold quality
periodontal ligament	UBERON:0008266	47.14	gold quality
renal glomerulus	UBERON:0000074	46.86	gold quality
metanephric glomerulus	UBERON:0004736	46.77	gold quality
nephron tubule	UBERON:0001231	46.71	gold quality
globus pallidus	UBERON:0001875	46.70	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	45.35	gold quality
inferior olivary complex	UBERON:0002127	45.14	gold quality
nasal cavity epithelium	UBERON:0005384	44.87	gold quality
amniotic fluid	UBERON:0000173	44.82	gold quality
tendon	UBERON:0000043	44.26	gold quality
ventricular zone	UBERON:0003053	43.39	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
bone marrow cell	CL:0002092	42.38	gold quality
metanephros	UBERON:0000081	42.07	gold quality
medulla oblongata	UBERON:0001896	41.74	gold quality
bone marrow	UBERON:0002371	41.60	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
colonic epithelium	UBERON:0000397	41.11	gold quality
smooth muscle tissue	UBERON:0001135	41.11	silver quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
popliteal artery	UBERON:0002250	40.88	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.46

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

6 targets.

Target	Regulation
BDNF	Activation
INA	Activation
LHX3	Activation
MYO6
NTF3
RIT2	Activation

JASPAR motifs

Motif	Name	Family
MA0791.1	POU4F3	POU domain factors
MA0791.2	POU4F3	POU domain factors

JASPAR matrix evidence (PMIDs): PMID:18077589

Upstream regulators (CollecTRI, top): ATOH1, POU4F1, POU4F2, TFAP2A, TFAP2D, YY1

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 29)

• Proneural and proneuroendocrine transcription factor expression in cutaneous mechanoreceptor (Merkel) cells and Merkel cell carcinoma (PMID:12209986)
• Mutant POU4F3 loses most of its transcriptional activity and most of its ability to bind to DNA. The mutation causes autosomal-dominant nonsyndromic hearing loss and eventually leads to hair cell morbidity in affected family H members. (PMID:14585957)
• Data show that Brn-3c is capable of activating both BDNF and NT-3 promoters in inner ear sensory epithelial cell lines. (PMID:15465029)
• our data show there are common sequence variants in the Brn-3c 5’-flanking region that affect transcriptional regulation in vitro (PMID:17611044)
• Mutation analysis of the POU4F3 gene in 30 patients suffering from dominantly inherited hearing impairment revealed a second novel missense mutation (c.668T>C). (PMID:18228599)
• report presents a detailed audiometric analysis of a Dutch family linked to DFNA15 with a novel mutation (p.L289F) in the POU4F3 gene (PMID:18347256)
• DFNA52 were mapped between STR D5S2056 and D5S638 on chromosome, and analysis candidate genes in this region did not reveal any potentially pathogenic mutations segregating with congenital sensorineural hearing loss. (PMID:19138900)
• extended subset of L289F POU4F3 mutation carriers varied from normal to areflexia in cochleovestibular disease (PMID:19372648)
• Cochleovestibular characteristics were investigated in a Dutch DFNA15 family with a novel POU4F3 mutation, L223P. (PMID:19462854)
• Molecular modelling is utilised to propose a mechanism of stability enhancement, via an interaction between the truncated POU(HD) domain and the POU(S) domain of the transcription factor. (PMID:20054994)
• This is the first report of a POU4F3 mutation in Asia, and moreover our data suggest that further investigation will need to delineate ethnicity-specific genetic background for autosomal dominant non-syndromic hearing loss within Asian populations. (PMID:20434433)
• SNP linkage analysis and whole exome sequencing identify a novel POU4F3 mutation in autosomal dominant late-onset nonsyndromic hearing loss (DFNA15). (PMID:24260153)
• new variants in genes such as POU4F3 is associated with nonsyndromic deafness and vestibular dysfunction (PMID:24275721)
• Data indicate that POUF4F3 deletion associated with hearing impairment. (PMID:24556497)
• The pou4f3 gene is regulated by ATOH1 and other transcription factors in cochlear hair cells. (PMID:25015561)
• These data demonstrate that Nr2f2 is a direct target of POU4F3 in vitro and that this regulatory relationship may be relevant to hair cell development and survival. (PMID:25372459)
• This study showed that Mendelian sensorineural hearing loss exhibits vestibular dysfunction, including DFNA9, DFNA11, DFNA15 and DFNA28. (PMID:27083884)
• results indicated GRHL2 might be a noise-induced hearing loss (NIHL) susceptibility gene, but the effect of POU4F3 on NIHL could only be detected when taking noise exposure into account and their effects were enhanced by higher levels of noise exposure (PMID:27271650)
• this study identified a novel heterozygous mutation (c.602delT, p.L201fs) in the gene POU4F3 within a large hearing impaired Chinese family. (PMID:27535032)
• report the first nonsense mutation of POU4F3 associated with progressive hearing loss and explored the possible underlying mechanism (PMID:27999687)
• Mutations in POU4F3 are a relatively common cause of autosomal dominant nonsyndromic hearing loss in Chinese Hans. (PMID:28053790)
• Novel 12 POU4F3 likely pathogenic variants (six missense variants, three frameshift variants, and three nonsense variants) were successfully identified in 15 probands (2.5%) among 602 families exhibiting autosomal dominant hearing loss, whereas no variants were detected in the other 1,947 probands with autosomal recessive or inheritance pattern unknown hearing loss. (PMID:28545070)
• Findings expanded the mutation spectrum of POU4F3 and suggest the pathogenesis associated with aberrant POU4F3 localization. (PMID:28790396)
• POU4F3 c.602T>C (p.Leu201Pro) is related to midfrequency hearing loss. (PMID:29850532)
• Identification of two novel mutations in POU4F3 gene associated with autosomal dominant hearing loss in Chinese families. (PMID:32390314)
• Four Novel Variants in POU4F3 Cause Autosomal Dominant Nonsyndromic Hearing Loss. (PMID:32684921)
• A Missense POU4F3 Variant Associated with Autosomal Dominant Midfrequency Hearing Loss Alters Subnuclear Localization and Transcriptional Capabilities. (PMID:34250087)
• Highly variable hearing loss due to POU4F3 (c.37del) is revealed by longitudinal, frequency specific analyses. (PMID:37072551)
• Ramifications of POU4F3 variants associated with autosomal dominant hearing loss in various molecular aspects. (PMID:37537203)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	pou4f3	ENSDARG00000006206
mus_musculus	Pou4f3	ENSMUSG00000024497
rattus_norvegicus	Pou4f3	ENSRNOG00000018842
drosophila_melanogaster	acj6	FBGN0000028
drosophila_melanogaster	vvl	FBGN0086680
caenorhabditis_elegans		WBGENE00000441
caenorhabditis_elegans		WBGENE00006818

Paralogs (17): POU2F2 (ENSG00000028277), POU1F1 (ENSG00000064835), POU6F2 (ENSG00000106536), POU2F3 (ENSG00000137709), POU2F1 (ENSG00000143190), POU4F2 (ENSG00000151615), POU4F1 (ENSG00000152192), HDX (ENSG00000165259), POU6F1 (ENSG00000184271), POU3F2 (ENSG00000184486), POU3F1 (ENSG00000185668), POU3F4 (ENSG00000196767), POU3F3 (ENSG00000198914), CCDC160 (ENSG00000203952), POU5F1 (ENSG00000204531), POU5F1B (ENSG00000212993), POU5F2 (ENSG00000248483)

Protein

Protein identifiers

POU domain, class 4, transcription factor 3 — Q15319 (reviewed: Q15319)

Alternative names: Brain-specific homeobox/POU domain protein 3C

All UniProt accessions (1): Q15319

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a transcriptional activator. Acts by binding to sequences related to the consensus octamer motif 5’-ATGCAAAT-3’ in the regulatory regions of its target genes. Involved in the auditory system development, required for terminal differentiation of hair cells in the inner ear.

Subunit / interactions. Interacts with ISL1.

Subcellular location. Nucleus. Cytoplasm.

Tissue specificity. Brain. Seems to be specific to the retina.

Disease relevance. Deafness, autosomal dominant, 15 (DFNA15) [MIM:602459] A form of non-syndromic hearing loss with variable phenotype in terms of age at onset, levels of progression, and shape of audiograms. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the POU transcription factor family. Class-4 subfamily.

RefSeq proteins (1): NP_002691* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000327	POU_dom	Domain
IPR001356	HD	Domain
IPR009057	Homeodomain-like_sf	Homologous_superfamily
IPR010982	Lambda_DNA-bd_dom_sf	Homologous_superfamily
IPR013847	POU	Domain
IPR017970	Homeobox_CS	Conserved_site
IPR050255	POU_domain_TF	Family

Pfam: PF00046, PF00157

UniProt features (20 total): sequence variant 15, chain 1, domain 1, sequence conflict 1, DNA-binding region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15319-F1	65.58	0.33

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 118 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, WWTAAGGC_UNKNOWN, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_RETINAL_GANGLION_CELL_AXON_GUIDANCE, GOBP_GROWTH, GOBP_NEUROGENESIS, CHX10_01, GOBP_CRANIAL_NERVE_DEVELOPMENT, GOBP_NEUROMUSCULAR_PROCESS_CONTROLLING_BALANCE, PAX8_B, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, CATRRAGC_UNKNOWN, GOBP_ANIMAL_ORGAN_MORPHOGENESIS

GO Biological Process (15): regulation of transcription by RNA polymerase II (GO:0006357), visual perception (GO:0007601), sensory perception of sound (GO:0007605), vestibulocochlear nerve development (GO:0021562), retinal ganglion cell axon guidance (GO:0031290), inner ear morphogenesis (GO:0042472), inner ear auditory receptor cell differentiation (GO:0042491), positive regulation of transcription by RNA polymerase II (GO:0045944), axon extension (GO:0048675), neuromuscular process controlling balance (GO:0050885), neuron apoptotic process (GO:0051402), regulation of DNA-templated transcription (GO:0006355), cell differentiation (GO:0030154), inner ear development (GO:0048839), inner ear receptor cell differentiation (GO:0060113)

GO Molecular Function (8): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), sequence-specific DNA binding (GO:0043565)

GO Cellular Component (4): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
inner ear development	2
regulation of transcription by RNA polymerase II	2
sensory perception of light stimulus	1
sensory perception of mechanical stimulus	1
cranial nerve development	1
axon guidance	1
ear morphogenesis	1
embryonic morphogenesis	1
hair cell differentiation	1
inner ear receptor cell differentiation	1
positive regulation of DNA-templated transcription	1
axonogenesis	1
neuron projection extension	1
musculoskeletal movement	1
neuromuscular process	1
apoptotic process	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
cellular developmental process	1
ear development	1
anatomical structure development	1
mechanoreceptor differentiation	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1
nucleic acid binding	1
binding	1
DNA binding	1

Protein interactions and networks

STRING

1136 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POU4F3	GFI1	Q99684	907
POU4F3	ATOH1	Q92858	814
POU4F3	MYO7A	P78427	789
POU4F3	DIAPH1	O60610	674
POU4F3	OTOF	Q9HC10	606
POU4F3	ESPN	B1AK53	604
POU4F3	SLC26A5	P58743	601
POU4F3	BARHL1	Q9BZE3	596
POU4F3	MYO6	Q9UM54	593
POU4F3	ATOH7	Q8N100	586
POU4F3	TMC1	Q8TDI8	583
POU4F3	KCNQ4	P56696	571
POU4F3	SLC17A8	Q8NDX2	558
POU4F3	MYO15A	Q9UKN7	546
POU4F3	GAP43	P17677	545

IntAct

27 interactions, top by confidence:

A	B	Type	Score
GOLGA2	POU4F3	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-3	POU4F3	psi-mi:“MI:0915”(physical association)	0.560
POU4F3	KRT31	psi-mi:“MI:0915”(physical association)	0.560
PLA2G10	POU4F3	psi-mi:“MI:0915”(physical association)	0.560
NHLRC4	POU4F3	psi-mi:“MI:0915”(physical association)	0.560
POU4F3	DUSP21	psi-mi:“MI:0915”(physical association)	0.560
POU4F3		psi-mi:“MI:0915”(physical association)	0.370
POU4F3	SNCG	psi-mi:“MI:0914”(association)	0.350
POU4F3	GOLGA2	psi-mi:“MI:0915”(physical association)	0.000
POU4F3	KRTAP6-3	psi-mi:“MI:0915”(physical association)	0.000
POU4F3	KRT31	psi-mi:“MI:0915”(physical association)	0.000
POU4F3	PLA2G10	psi-mi:“MI:0915”(physical association)	0.000
POU4F3	NHLRC4	psi-mi:“MI:0915”(physical association)	0.000
POU4F3	DUSP21	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (12): POU4F3 (Reconstituted Complex), POU4F3 (Two-hybrid), KRT31 (Two-hybrid), GOLGA2 (Two-hybrid), DUSP21 (Two-hybrid), KRTAP6-3 (Two-hybrid), NHLRC4 (Two-hybrid), HIST1H2AG (Affinity Capture-MS), SNCG (Affinity Capture-MS), S100A4 (Affinity Capture-MS), POU4F3 (Affinity Capture-MS), POU4F3 (Affinity Capture-MS)

ESM2 similar proteins: A0A1L8FFY5, A1L0Z1, A1L1N5, A4IFD2, A8XJD0, B3DM25, B7ZQA9, D3ZTL1, P10037, P20268, P20912, P23899, P24350, P27889, P31362, P31363, P31364, P31365, P31369, P35680, P42571, P49335, P56224, P62515, P62516, P70030, P79364, P79745, P79746, Q00196, Q03365, Q05041, Q08478, Q15319, Q2LE08, Q4QQQ7, Q561L5, Q5RER5, Q5W1J5, Q6DJN3

Diamond homologs: A0A1L8FFY5, A1L0Z1, A7Y7W2, B3DM23, B3DM25, B7ZQA9, D3ZTL1, G3V7L5, O97552, P09086, P10036, P10037, P13528, P14859, P15143, P16143, P16241, P17208, P20263, P20264, P20265, P20266, P20267, P20268, P20912, P20913, P20914, P21952, P24350, P25425, P28069, P31360, P31361, P31362, P31363, P31364, P31365, P31367, P31368, P31369

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
POU4F3	“up-regulates quantity by expression”	LHX3	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

182 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	14
Uncertain significance	102
Likely benign	31
Benign	6

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1366764	NM_002700.3(POU4F3):c.246_645delinsGG (p.Met83fs)	Pathogenic
2424524	NC_000005.9:g.(?145718676)(145718815_?)del	Pathogenic
2869928	NM_002700.3(POU4F3):c.414_418del (p.Val139fs)	Pathogenic
3336609	NM_002700.3(POU4F3):c.602del (p.Leu201fs)	Pathogenic
3336612	NM_002700.3(POU4F3):c.879C>A (p.Phe293Leu)	Pathogenic
3601695	NM_002700.3(POU4F3):c.592C>A (p.Arg198Ser)	Pathogenic
3601700	NM_002700.3(POU4F3):c.976A>G (p.Arg326Gly)	Pathogenic
3651184	NM_002700.3(POU4F3):c.218del (p.Pro73fs)	Pathogenic
4072367	NM_002700.3(POU4F3):c.288dup (p.Ile97fs)	Pathogenic
7079	NM_002700.3(POU4F3):c.865C>T (p.Leu289Phe)	Pathogenic
1065044	NM_002700.3(POU4F3):c.545C>G (p.Ser182Ter)	Likely pathogenic
1297744	NM_002700.3(POU4F3):c.952G>A (p.Val318Met)	Likely pathogenic
2507263	NM_002700.3(POU4F3):c.703_704del (p.Thr235fs)	Likely pathogenic
2574954	NM_002700.3(POU4F3):c.982A>G (p.Lys328Glu)	Likely pathogenic
3024075	NM_002700.3(POU4F3):c.494_497del (p.His165fs)	Likely pathogenic
3383007	NM_002700.3(POU4F3):c.337C>T (p.Gln113Ter)	Likely pathogenic
3601692	NM_002700.3(POU4F3):c.296_297dup (p.Pro100fs)	Likely pathogenic
3601694	NM_002700.3(POU4F3):c.413C>A (p.Ser138Ter)	Likely pathogenic
3601696	NM_002700.3(POU4F3):c.592C>G (p.Arg198Gly)	Likely pathogenic
3601702	NM_002700.3(POU4F3):c.97C>T (p.Arg33Ter)	Likely pathogenic
4087746	NM_002700.3(POU4F3):c.932T>C (p.Leu311Pro)	Likely pathogenic
4282444	NM_002700.3(POU4F3):c.282del (p.Val95fs)	Likely pathogenic
444664	NM_002700.3(POU4F3):c.118C>T (p.Gln40Ter)	Likely pathogenic
4537383	NM_002700.3(POU4F3):c.528C>A (p.Cys176Ter)	Likely pathogenic

SpliceAI

226 predictions. Top by Δscore:

Variant	Effect	Δscore
5:146339232:GGTA:G	donor_loss	1.0000
5:146339233:G:GA	donor_loss	1.0000
5:146339234:T:G	donor_loss	1.0000
5:146339229:GCAG:G	donor_gain	0.9900
5:146339546:A:AG	acceptor_gain	0.9800
5:146339546:AGCT:A	acceptor_gain	0.9800
5:146339547:G:GG	acceptor_gain	0.9800
5:146339547:GC:G	acceptor_gain	0.9800
5:146339547:GCT:G	acceptor_gain	0.9800
5:146339547:GCTG:G	acceptor_gain	0.9800
5:146339547:GCTGC:G	acceptor_gain	0.9800
5:146339233:G:GG	donor_gain	0.9700
5:146339543:TGCA:T	acceptor_loss	0.9600
5:146339544:GCA:G	acceptor_loss	0.9600
5:146339545:CAGCT:C	acceptor_loss	0.9600
5:146339539:C:A	acceptor_loss	0.9400
5:146339539:C:CA	acceptor_gain	0.9100
5:146339228:CGCAG:C	donor_gain	0.9000
5:146339229:GCAGG:G	donor_gain	0.9000
5:146339549:T:A	acceptor_gain	0.8900
5:146339231:AG:A	donor_gain	0.8500
5:146339232:GG:G	donor_gain	0.8500
5:146339543:T:TA	acceptor_gain	0.8300
5:146339099:CCAGG:C	acceptor_gain	0.8000
5:146339230:CAG:C	donor_gain	0.7900
5:146338961:A:G	donor_gain	0.7800
5:146339506:A:AG	acceptor_gain	0.7800
5:146339507:G:GG	acceptor_gain	0.7800
5:146339102:GGAGC:G	acceptor_gain	0.7700
5:146339089:T:A	acceptor_gain	0.7500

AlphaMissense

2226 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:146339987:T:C	L187P	1.000
5:146339995:T:C	F190L	1.000
5:146339996:T:C	F190S	1.000
5:146339997:C:A	F190L	1.000
5:146339997:C:G	F190L	1.000
5:146339999:C:A	A191D	1.000
5:146340007:T:C	F194L	1.000
5:146340008:T:C	F194S	1.000
5:146340009:C:A	F194L	1.000
5:146340009:C:G	F194L	1.000
5:146340010:A:G	K195E	1.000
5:146340011:A:T	K195M	1.000
5:146340012:G:C	K195N	1.000
5:146340012:G:T	K195N	1.000
5:146340017:G:C	R197P	1.000
5:146340019:C:A	R198S	1.000
5:146340019:C:G	R198G	1.000
5:146340020:G:A	R198H	1.000
5:146340020:G:C	R198P	1.000
5:146340023:T:A	I199N	1.000
5:146340023:T:C	I199T	1.000
5:146340023:T:G	I199S	1.000
5:146340029:T:C	L201P	1.000
5:146340031:G:A	G202R	1.000
5:146340031:G:C	G202R	1.000
5:146340031:G:T	G202W	1.000
5:146340032:G:A	G202E	1.000
5:146340032:G:T	G202V	1.000
5:146340038:C:T	T204I	1.000
5:146340042:G:C	Q205H	1.000

dbSNP variants (sampled 300 via entrez): RS1000371396 (5:146340777 C>T), RS1000704340 (5:146342172 G>A), RS1001104547 (5:146338962 T>A,C,G), RS1001249462 (5:146341163 T>C), RS1001741580 (5:146341437 A>G), RS1001975970 (5:146339400 C>T), RS1002092278 (5:146337110 A>G,T), RS1002317071 (5:146337425 G>A), RS1002917982 (5:146341962 A>G,T), RS1003910351 (5:146339485 G>A,T), RS1004169957 (5:146338492 G>A,C,T), RS1004664999 (5:146340506 G>T), RS1005060128 (5:146341504 T>A,C), RS1005366997 (5:146337454 G>A), RS1005583454 (5:146340936 A>G)

Disease associations

OMIM: gene MIM:602460 | disease phenotypes: MIM:602459

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss 15	Definitive	Autosomal dominant
nonsyndromic genetic hearing loss	Definitive	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Definitive	AD

Mondo (4): hearing loss disorder (MONDO:0005365), autosomal dominant nonsyndromic hearing loss 15 (MONDO:0011226), nonsyndromic genetic hearing loss (MONDO:0019497), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (1): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000365	Hearing impairment

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007540_4	PEG-asparaginase hypersensitivity without enzyme activity in childhood acute lymphoblastic leukaemia	3.000000e-06
GCST008359_7	Response to cognitive-behavioural therapy in anxiety disorder	4.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004881	asparaginase hypersensitivity
EFO:0007820	cognitive behavioural therapy

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C566545	Deafness, Autosomal Dominant 15 (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation	1
butyraldehyde	increases expression	1
CGP 52608	affects binding, increases reaction	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Plant Extracts	increases expression	1
Tetrachlorodibenzodioxin	decreases expression	1
Tetradecanoylphorbol Acetate	affects cotreatment, affects expression	1
Valproic Acid	decreases methylation	1
Zinc	affects cotreatment, affects expression	1
Aflatoxin B1	decreases methylation	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A5M8	SEES3-1V human POU4F3, clone1	Embryonic stem cell	Male
CVCL_A5M9	SEES3-1V human POU4F3, clone2	Embryonic stem cell	Male
CVCL_A5N0	SEES3-1V human POU4F3, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma
NCT07304024	PHASE1/PHASE2	RECRUITING	A Treatment for a Form of Age-Related Central Auditory Processing Disorder Consisting of Clemastine Fumarate Plus Engineered Sound