• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
POU4F3 (HGNC:9220) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
POU class 4 homeobox 3
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
DFNA15, DFNA52, DFNA42
Alias symbols
BRN3C
%HI
8.21(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.92(Read more about gnomAD pLI score)
LOEUF
0.37(Read more about gnomAD LOEUF score)
Cytoband
5q32
Genomic Coordinates
GRCh37/hg19: chr5:145718402-145721291 NCBI Ensembl UCSC
GRCh38/hg38: chr5:146338839-146341728 NCBI Ensembl UCSC
MANE Select Transcript
NM_002700.3 ENST00000646991.2 (Read more about MANE Select)
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}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-34906
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
11/29/2023

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • DEAFNESS, AUTOSOMAL DOMINANT 15 Monarch
HI Evidence:
  • PUBMED: 9506947
    Vahava et al. 1998 (PMID: 9506947) first reported a large Jewish Israeli family with a c.882_889delTATCCAGC p.(Ile295ThrfsX5) variant segregating with autosomal dominant progressive deafness in 17 segregations. Onset was between 18 and 30 years, and hearing loss was moderate to severe by 50 years. All individuals with normal hearing over 40 years old did not carry the variant.
  • PUBMED: 27535032
    Cai et al. 2017 (PMID: 27535032) identified a five generation Chinese family with a c.602delT p.(Leu201Argfs) variant segregating with autosomal dominant progressive hearing loss in 19 family members. WES was performed on 2 affected and one unaffected, and the other family members were confirmed by Sanger sequencing. Hearing loss onset ranged from 16 to 30 years. Additional clinical information can be found in Xia et al. 2001 (PMID: 12522684).
  • PUBMED: 27999687
    Zhang et al. 2016 (PMID: 27999687) studied a four generation Chinese family with autosomal dominant moderate to severe hearing loss. The age of onset was variable, from 14 to 40 years. Four affected and 8 unaffected members were willing to participate. The researchers used targeted NGS of 81 genes in the proband, and Sanger sequenced the other participating members. They identified a c.337C>T p.(Gln113X) variant in POU4F3 that segregated with disease. One family member carried the variant but was younger than the age of onset.
  • PUBMED: 24556497
    Freitas et al. (PMID: 24556497) identified a 56kb deletion including POU4F3 in a father and son with post-lingual hearing loss. Presence of the deletion was confirmed by qRT-PCR and contained no other coding loci annotated by RefSeq. Age of onset was 11-13.
  • PUBMED: 32684921
    Cui et al. (PMID: 32684921) identified c.183delG p.(Ala62ArgfsX22) variant in a Chinese family with progressive, adult onset hearing loss. The variant was identified in affected individuals across four segregations.
  • PUBMED: 28545070
    Kitano et al. (PMID: 28545070) identified several damaging POU4F3 variants, including three nonsense and three frameshift variants, in a cohort of 602 individuals recruited for hearing loss. Co-segregation evidence could not be obtained, though familial clinical evaluations are consistent with autosomal dominant transmission.
HI Evidence Comments:
Bai et al. 2020 (PMID: 32390314) describes a three generation Chinese family with dominantly transmitted adult onset hearing loss. A candidate frameshift variant in POU4F3, c.709_710del; p.(Ser237AlafsX65), was identified by NGS sequencing, and subsequent family members tested via Sanger. The variant segregated with disease in 4 individuals. Note the variant was reported with non-HGVS compliant nomenclature: c.704_705del; (p.T235fs). Also described as "p.235_235del." Multiple loss of function POU4F3 variants have been associated with autosomal dominant nonsyndromic hearing loss (ADNSHL), including nonsense, frameshift, and large deletion variants, suggesting haploinsufficiency as the mechanism of disease. Multiple mouse studies, however, show that mice only require one functional copy of the gene to retain hearing (Erkman et al 1997; PMID: 8637595, and Hertzano et al 200; PMID: 15254021). The overall evidence that POU4F3, when altered, causes ADNSHL has been Expert reviewed as Definitive by the ClinGen Hearing Loss Gene Curation Working Group.

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000005.9) (NC_000005.10)