POU3F3
protein-codingPOU class 3 homeobox 3, the group of POU class homeoboxes and pseudogenes
Gene summary
This gene encodes a POU-domain containing protein that functions as a transcription factor. The encoded protein recognizes an octamer sequence in the DNA of target genes. This protein may play a role in development of the nervous system. [provided by RefSeq, Apr 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~5.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0032830
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
*POU3F3* (also known as *BRN1*) was first reported in relation to an autosomal dominant complex neurodevelopmental disorder, also called Snijders Blok-Fisher Syndrome, in 2019 (Snijders et al., PMID: 31303265). *POU3F3* only has one coding exon. Probands with variants in *POU3F3* are characterized mainly by global developmental delay/intellectual disability, impaired speech and language acquisition, and hypotonia. Additional features can include dysmorphisms, gastrointestinal comorbidities, hearing loss, ophthalmological anomalies, epilepsy, sleep disturbances and joint hypermobility. Nine variants (3 missense, 1 in-frame indel, 1 nonsense, 4 frameshift) that have been reported in 10 probands in 3 publications (PMIDs: 31303265, 33645921, 37165752) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In most of the reported patients, purported truncating variants were detected but missense variants have also been reported in the POU-S and POU-H domains. Functional assays showed truncating variants affected subcellular localization, dimerization, and transcriptional activation while some missense variants showed decreased or increased transcriptional activation in a luciferase assay. The mechanism of pathogenicity is consistent with loss-of-function although the mechanism for several missense variants is unclear and requires further investigation. There is no scorable experimental evidence to support this gene-disease relationship. Expression studies have demonstrated expression in the neocortex but were not scored per the Intellectual Disability and Autism GCEP’s guidelines on not scoring expression because most genes are expressed in the brain. Additionally, complete homozygous pou3f3 (Brn1) knockout mouse embryos showed disorganized cortical lamination while heterozygous knockout mice showed no clinical features (PMID: 11859196). Brain structural aberrations such as dilation of ventricles, thin corpus callosum, and cerebral atrophy were observed in some patients affected by this disorder. However, due to lack of specificity in the phenotypic overlap and construct validity, the mice are homozygous and humans are heterozygous, this mouse model was not scored. In summary, there is definitive evidence supporting the relationship between *POU3F3* and an autosomal dominant complex neurodevelopmental disorder. 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 Intellectual Disability and Autism GCEP on June 13, 2024 (SOP Version 10).
Inheritance Pattern: AD
Disease ID:MONDO:0032830
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0032830
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0032830
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0032830
Submitter: Illumina
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to POU3F3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006236.3. 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 | 34 | 1 | 35 | |||
| missense | 2 | 19 | 155 | 5 | 181 | |
| nonsense | 6 | 7 | 2 | 15 | ||
| start loss | 1 | 1 | ||||
| frameshift | 10 | 12 | 2 | 24 | ||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 18 | 38 | 160 | 39 | 1 | 256 |
Highest pathogenic variant AF is 0.000003730522
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006227.1 | 1 | MANE Select | |
| Ensembl | ENSP00000355001.2 | 1 | MANE Select | |
| RefSeq | NP_001420633.1 | 1 | Standard | |
| Ensembl | ENSP00000501036.1 | 1 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- central nervous system development
- excretion
- positive regulation of cell population proliferation
- positive regulation of gene expression
- cerebral cortex radially oriented cell migration
Molecular Function
- DNA-binding transcription factor activity, RNA polymerase II-specific
- DNA-binding transcription factor activity
- sequence-specific DNA binding
- HMG box domain binding
Cellular Component
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000361360
- Coding exons
- 1
- Length
- 4961
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.04 | 63 | 177 | 0.356 | 0.00000821 | 3161 |
| Missense (PolyPhen) | 5 | 59.109 | 0.084589 | 753 | ||
| Synonymous | -0.602 | 92 | 84.9 | 1.08 | 0.00000412 | 1059 |
| Loss of Function | 2.45 | 0 | 6.98 | 0.00 | 3.04e-7 | 103 |
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 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Transcription factor that acts synergistically with SOX11 and SOX4. Plays a role in neuronal development. Is implicated in an enhancer activity at the embryonic met- mesencephalic junction; the enhancer element contains the octamer motif (5'-ATTTGCAT-3') (By similarity). {ECO:0000250}.;
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.927
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |