POU4F3

protein-coding

POU class 4 homeobox 3, the group of POU class homeoboxes and pseudogenes

Gene summary

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. [provided by RefSeq, Mar 2009]

Previous symbols:

DFNA15
DFNA52
DFNA42

MANE transcript

NM_002700.3

Inheritance

ClinVar variants

P:64U:151B:61

Top phenotype

Deafness, autosomal dominant 15

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr5:146,338,839-146,341,728

External References & Databases

Ensembl (ENSG00000091010)

Transcript & Mutation Effects

hg38 • Region Span ~2.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant nonsyndromic hearing loss 15STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011226

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

autosomal dominant nonsyndromic hearing loss 15STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011226

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 15DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011226

Submitter: Ambry Genetics

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

The POU4F3 gene has been associated with autosomal dominant nonsyndromic hearing loss DFNA15 in at least 18 probands in 18 publications. Missense, in-frame indel, nonsense, frameshift, large deletion variants have been reported in humans, and variants in this gene segregated with disease in over 60 additional family members. POU4F3 was first associated with this disease in humans in 1998 (Vahava et al.). The hearing loss in DFNA15 individuals is progressive, with a highly variable age of onset between the second and fifth decades of life. The mechanism for disease is likely haploinsufficiency, due to the wide variant spectrum, however mice require only one copy of the functional gene to retain hearing (Erkman 1997, Keithley 1999, Hertzano 2004). This gene-disease association is supported by multiple mouse models, expression studies, and in vitro functional assays. In summary, POU4F3 is definitively associated with autosomal dominant nonsyndromic sensorineural 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 11/21/2017.

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 15AD

Manifestation: Audiologic/Otolaryngologic

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

Refs: 9506947; 18228599; 18347256; 19372648; 19462854; 20434433; 22938506

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POU4F3 variants in ClinVar

11 Conditions Cataloged

not providedTotal: 159

Autosomal dominant nonsyndromic hearing loss 15Total: 83

Inborn genetic diseasesTotal: 50

not specifiedTotal: 40

POU4F3-related disorderTotal: 28

Hearing impairmentTotal: 5

Monogenic hearing lossTotal: 2

Rare genetic deafnessTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002700.3. 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			4 clinvar	50 clinvar	4 clinvar	58
missense	6 clinvar	17 clinvar	146 clinvar	7 clinvar		176
nonsense	3 clinvar	10 clinvar				13
start loss						0
frameshift	18 clinvar	10 clinvar	1 clinvar			29
splice donor/acceptor (+/-2bp)						0
Total	27	37	151	57	4	276

Highest pathogenic variant AF is 0.000006570907

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 3 of 3 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002700.3	RefSeq	NP_002691.1	2	MANE Select
ENST00000646991.2	Ensembl	ENSP00000495718.1	2	MANE Select
ENST00000914229.1	Ensembl	ENSP00000584288.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

visual perception
sensory perception of sound
vestibulocochlear nerve development
retinal ganglion cell axon guidance
inner ear morphogenesis

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription activator activity, RNA polymerase II-specific
DNA-binding transcription factor activity

Cellular Component

nucleus
nucleoplasm
cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000230732
Coding exons: 2
Length: 1497
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125732
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.661	208	183	1.14	0.00000939	2210
Missense (PolyPhen)		40	54.595	0.73266		688
Synonymous	-2.74	105	74.8	1.40	0.00000438	698
Loss of Function	2.63	0	8.08	0.00	3.79e-7	93

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a transcriptional activator (PubMed:18228599). Acts by binding to sequences related to the consensus octamer motif 5'-ATGCAAAT-3' in the regulatory regions of its target genes (PubMed:18228599). Involved in the auditory system development, required for terminal differentiation of hair cells in the inner ear (By similarity). {ECO:0000250|UniProtKB:Q63955, ECO:0000269|PubMed:18228599}.;

Recessive Scores

pRec: 0.156

Intolerance Scores

LoFtool: 0.111
RVIS EVS: -0.54
RVIS percentile EVS: 20.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.431

Gene Damage Prediction

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