BPTF
protein-codingbromodomain PHD finger transcription factor, the group of PHD finger proteins|Bromodomain containing|NURF complex
Gene summary
This gene was identified by the reactivity of its encoded protein to a monoclonal antibody prepared against brain homogenates from patients with Alzheimer's disease. Analysis of the original protein (fetal Alz-50 reactive clone 1, or FAC1), identified as an 810 aa protein containing a DNA-binding domain and a zinc finger motif, suggested it might play a role in the regulation of transcription. High levels of FAC1 were detected in fetal brain and in patients with neurodegenerative diseases. The protein encoded by this gene is actually much larger than originally thought, and it also contains a C-terminal bromodomain characteristic of proteins that regulate transcription during proliferation. The encoded protein is highly similar to the largest subunit of the Drosophila NURF (nucleosome remodeling factor) complex. In Drosophila, the NURF complex, which catalyzes nucleosome sliding on DNA and interacts with sequence-specific transcription factors, is necessary for the chromatin remodeling required for transcription. Two alternative transcripts encoding different isoforms have been described completely. [provided by RefSeq, Jul 2008]
- FALZ
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~158.9 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0060596
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0060596
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0060596
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0000508
Submitter: ClinGen
*BPTF* was first reported in relation to autosomal dominant syndromic intellectual disability in 2017 (Stankiewicz et al., PMID: 28942966). *BPTF* encodes the largest subunit of the nucleosome remodeling complex (NURF), a highly conserved chromatin remodeling complex involved in regulation of transcription. Individuals with variants in *BPTF* are reported to present with a phenotypic spectrum including developmental delay/intellectual disability, speech/language delay, motor delay, hypotonia, microcephaly, dysmorphic features, and variable distal limb anomalies including fifth digit clinodactyly and sandal gap. *BPTF* has been noted to be associated with the following disease entities: neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (OMIM:617755), and non-specific syndromic intellectual disability (ORPHA:528084). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the above disease entities have been lumped into one disease entity, syndromic intellectual disability (MONDO:0000508), given that this term captures the neurodevelopmental and syndromic findings reported in the literature to date. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Seven variants (e.g., frameshift, nonsense, missense) reported in 8 probands (PMIDs: 28942966, 33522091) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by both non-mammalian and mammalian model systems (PMIDs: 28942966, 35604347). In summary, there is definitive evidence to support the relationship between *BPTF* and autosomal dominant syndromic intellectual disability. 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 Intellectual Disability and Autism Gene Curation Expert Panel on 7/6/2022 (SOP Version 9).
Inheritance Pattern: AD
Disease ID:MONDO:0000508
Submitter: Illumina
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; Neurologic; Oncologic; Ophthalmologic
Intervention: Oncologic
Rationale: Individuals have been described as susceptible to Kaposi sarcoma, and awareness may enable prompt diagnosis and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to BPTF variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_182641.4. 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 | 7 | 168 | 15 | 190 | ||
| missense | 15 | 701 | 111 | 12 | 839 | |
| nonsense | 8 | 13 | 5 | 26 | ||
| start loss | 2 | 2 | ||||
| frameshift | 33 | 21 | 3 | 57 | ||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 6 | 10 | ||
| Total | 42 | 52 | 724 | 279 | 27 | 1124 |
Highest pathogenic variant AF is 0.00051948754
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_872579.2 | 28 | MANE Select | |
| Ensembl | ENSP00000307208.6 | 28 | MANE Select | |
| RefSeq | NP_001426068.1 | 29 | Standard | |
| RefSeq | NP_001426069.1 | 31 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| bptf | Danio rerio | Structure: spinal cord neural keel Quality: decreased size abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Endoderm Differentiation
Biological Process
- negative regulation of transcription by RNA polymerase II
- embryonic placenta development
- chromatin remodeling
- regulation of transcription by RNA polymerase II
- brain development
Molecular Function
- protein binding
- DNA-dependent ATPase activity
- transcription factor binding
- methylated histone binding
- sequence-specific DNA binding
Cellular Component
- nuclear chromatin
- nucleus
- nucleoplasm
- cytoplasm
- NURF complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000306378
- Coding exons
- 28
- Length
- 158855
- Individuals with no LoFs
- 125733
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 13
- Defined
- 125746
- p
- 0.0000517
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 3.71 | 1067 | 1.47e+3 | 0.727 | 0.0000764 | 19141 |
| Missense (PolyPhen) | 373 | 663.19 | 0.56243 | 8494 | ||
| Synonymous | -0.479 | 547 | 533 | 1.03 | 0.0000284 | 5675 |
| Loss of Function | 10.1 | 7 | 133 | 0.0527 | 0.00000766 | 1571 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.00022 | 0.00017 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000028 | 0.000026 | rare |
| South Asian | 0.000098 | 0.000098 | rare |
| Other | 0.00017 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Histone-binding component of NURF (nucleosome-remodeling factor), a complex which catalyzes ATP-dependent nucleosome sliding and facilitates transcription of chromatin. Specifically recognizes H3 tails trimethylated on 'Lys-4' (H3K4me3), which mark transcription start sites of virtually all active genes. May also regulate transcription through direct binding to DNA or transcription factors.;
- Disease
- DISEASE: Neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (NEDDFL) [MIM:617755]: An autosomal dominant neurodevelopmental disorder characterized by variable degrees of developmental delay, intellectual disability, speech delay, postnatal microcephaly, dysmorphic features, and mild abnormalities of the hands and feet. {ECO:0000269|PubMed:28942966}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.131
Intolerance Scores
- LoFtool
- 0.278
- RVIS EVS
- -2.55
- RVIS percentile EVS
- 0.86
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- S
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.860
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |