POU4F3

Chr 5AD

POU class 4 homeobox 3

Also known as: BRN3C, DFNA15, DFNA42, DFNA52

NCBI Gene: 5459 ENSG00000091010 UniProt: Q15319 OMIM: 602460

This gene encodes a POU-domain transcription factor that acts as a transcriptional activator by binding to octamer motifs in target gene regulatory regions and is required for terminal differentiation of hair cells in the inner ear. Mutations cause autosomal dominant non-syndromic sensorineural hearing loss (DFNA15/52). The gene is highly constrained against loss-of-function variants (pLI 0.92, LOEUF 0.37), indicating intolerance to functional disruption.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Deafness, autosomal dominant 15/52MIM #602459

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · nonsyndromic genetic hearing loss · AD · ClinGen 2017

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.37

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.37LOEUF

pLI 0.920

Z-score 2.63

OE 0.00 (0.00–0.37)

Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

-0.66Z-score

OE missense 1.14 (1.01–1.28)

208 obs / 182.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.37)

0≤0.351.4

Missense OE?1.14 (1.01–1.28)

0≤0.61.4

Synonymous OE?1.40

0≤1.21.6

LoF obs/exp: 0 / 8.1Missense obs/exp: 208 / 182.8Syn Z: -2.74

Background carrier burden — how many people carry a rare variant somewhere in POU4F3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 180

491 rare PASS variants

Rare truncating (LoF)

1 in 22,000

21 rare PASS variants

Rare synonymous (reference)

1 in 190

234 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for POU4F3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 290	1 in 16,000
South Asian	~43k	1 in 160	none seen
Remaining (unassigned)	~30k	1 in 130	none seen
European (Finnish)	~27k	1 in 860	≈ 1 in 12,000
Admixed American	~22k	1 in 170	none seen
African / African American	~21k	1 in 170	≈ 1 in 5,600
East Asian	~20k	1 in 110	none seen
Ashkenazi Jewish	~13k	1 in 770	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 180	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓