PHF6
protein-codingPHD finger protein 6, the group of PHD finger proteins
Gene summary
This gene is a member of the plant homeodomain (PHD)-like finger (PHF) family. It encodes a protein with two PHD-type zinc finger domains, indicating a potential role in transcriptional regulation, that localizes to the nucleolus. Mutations affecting the coding region of this gene or the splicing of the transcript have been associated with Borjeson-Forssman-Lehmann syndrome (BFLS), a disorder characterized by cognitive disability, epilepsy, hypogonadism, hypometabolism, obesity, swelling of subcutaneous tissue of the face, narrow palpebral fissures, and large ears. Alternate splicing results in multiple transcript variants, encoding different isoforms. [provided by RefSeq, Jun 2010]
- BFLS
- BORJ
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~55.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010537
Submitter: Genomics England PanelApp
Inheritance Pattern: XL
Disease ID:MONDO:0010537
Submitter: Illumina
Inheritance Pattern: XL
Disease ID:MONDO:0010537
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010537
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0010537
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010537
Submitter: ClinGen
*PHF6* was first reported in relation to X-linked Börjeson-Forssman-Lehmann syndrome in 2002 (Lower et al., PMID: 12415272). *PHF6* encodes a protein involved in transcriptional regulation. Börjeson-Forssman-Lehmann syndrome is characterized by intellectual disability, epilepsy, obesity, hypogonadism, characteristic facial features with narrow palpebral fissures, tapered fingers and short toes. Heterozygote females may exhibit a similar but milder clinical phenotype; however, many carrier females appear unaffected. Nine variants (nonsense, frameshift, splice, missense, start loss) that have been reported in 13 probands in five publications (PMIDs: 12415272, 15241480, 15466013, 15994862, 23906836) are included in this curation. The p.Arg342* variant is recurrent and was reported in three unrelated families (PMID: 15241480). Variants in this gene segregated with disease in additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by experimental evidence, including a mouse model showing that loss of PHF6 impairs neuronal migration in the brain, and protein interaction with the NuRD complex (PMIDs: 22720776, 23791194). In summary, there is definitive evidence supporting the relationship between *PHF6* and X-linked Börjeson-Forssman-Lehmann syndrome. 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 Gene Curation Expert Panel on February 21, 2018 (SOP Version 5). As of July 2022, this record underwent administrative updates to include an evidence summary text and update scoring to be consistent with SOP Version 9. No new evidence has been added.
Inheritance Pattern: XL
Disease ID:MONDO:0010537
Submitter: PanelApp Australia
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Endocrine; Musculoskeletal; Neurologic
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 PHF6 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001015877.2. 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 | 1 | 12 | 50 | 3 | 66 | |
| missense | 10 | 11 | 130 | 9 | 160 | |
| nonsense | 14 | 4 | 8 | 26 | ||
| start loss | 2 | 1 | 3 | |||
| frameshift | 7 | 2 | 4 | 13 | ||
| splice donor/acceptor (+/-2bp) | 3 | 4 | 20 | 27 | ||
| Total | 36 | 22 | 175 | 59 | 3 | 295 |
Highest pathogenic variant AF is 9.507113e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001015877.1 | 9 | MANE Select | |
| Ensembl | ENSP00000359839.4 | 9 | MANE Select | |
| RefSeq | NP_115711.2 | 7 | Standard | |
| RefSeq | NP_115834.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Mesodermal Commitment Pathway
Biological Process
- negative regulation of transcription by RNA polymerase II
- blastocyst hatching
Molecular Function
- DNA-binding transcription repressor activity, RNA polymerase II-specific
- RNA binding
- protein binding
- tubulin binding
- enzyme binding
Cellular Component
- condensed chromosome kinetochore
- nucleus
- nucleoplasm
- nucleolus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000332070
- Coding exons
- 9
- Length
- 55538
- 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 | 2.28 | 57 | 130 | 0.437 | 0.00000914 | 2412 |
| Missense (PolyPhen) | 5 | 52.447 | 0.095334 | 993 | ||
| Synonymous | -0.502 | 48 | 43.8 | 1.10 | 0.00000300 | 645 |
| Loss of Function | 3.93 | 0 | 18.0 | 0.00 | 0.00000173 | 281 |
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: Transcriptional regulator that associates with ribosomal RNA promoters and suppresses ribosomal RNA (rRNA) transcription. {ECO:0000269|PubMed:23229552}.;
- Disease
- DISEASE: Boerjeson-Forssman-Lehmann syndrome (BFLS) [MIM:301900]: A X-linked recessive disorder characterized by moderate to severe mental retardation, epilepsy, hypogonadism, hypometabolism, obesity with marked gynecomastia, swelling of subcutaneous tissue of the face, narrow palpebral fissure and large but not deformed ears. {ECO:0000269|PubMed:12415272, ECO:0000269|PubMed:23229552, ECO:0000269|PubMed:23906836}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.163
Intolerance Scores
- LoFtool
- 0.142
- RVIS EVS
- -0.03
- RVIS percentile EVS
- 51.04
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- N
- Indispensability score
- 0.114
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |