GeneBe

PHF8

protein-coding

PHD finger protein 8, the group of Lysine demethylases|PHD finger proteins

Gene summary

The protein encoded by this gene is a histone lysine demethylase that preferentially acts on histones in the monomethyl or dimethyl states. The encoded protein requires Fe(2+) ion, 2-oxoglutarate, and oxygen for its catalytic activity. The protein has an N-terminal PHD finger and a central Jumonji C domain. This gene is thought to function as a transcription activator. Defects in this gene are a cause of syndromic X-linked Siderius type intellectual disability (MRXSSD) and over-expression of this gene is associated with several forms of cancer. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

MANE transcript

NM_015107.3

Inheritance

XL

ClinVar variants

P:34U:250B:77

Top phenotype

Intellectual developmental disorder, X-linked, syndrome, Siderius type

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chrX:53,936,676-54,048,958

External References & Databases

Ensembl (ENSG00000172943)NCBI Gene (23133)OMIM (300560)HGNC:20672GenCCUniProt (Q9UPP1)AlphaFoldClinVar (PHF8)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~112.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked, syndromic, Siderius typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010286

Submitter: ClinGen

*PHF8* is located on chromosome Xp11.22 and encodes a histone lysine demethylase that plays a role in the regulation of gene expression. *PHF8* was first reported in relation to syndromic X-linked intellectual disability, Siderius type in 2005 (Laumonnier et al., PMID: 16199551) in the family reported by Siderius et al. (1999, PMID: 10398231) and in another family with similar features. Affected males typically have developmental delay with speech delay, intellectual disability, and craniofacial dysmorphism, which can include cleft lip/palate, long face, microcephaly, hypertelorism, broad nasal bridge, retrognathia, and low-set ears. Female carriers are unaffected. Nine variants (nonsense, frameshift, splice, and missense) that have been reported in nine probands in six publications (PMIDs: 16199551, 17594395, 17661819, 25167861, 26633542, 29276005) are included in this curation. Variants in this gene segregated with disease in three additional family members. The mechanism of pathogenicity is loss of function. This gene-disease relationship is also supported by mouse and zebrafish models, protein interaction, and functional alterations in non-patient cells. In summary, there is definitive evidence supporting the relationship between *PHF8* and syndromic X-linked intellectual disability, Siderius type. 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 November 7, 2018 (SOP Version 6). As of February 2026, this record underwent administrative updates to update scoring to be consistent with SOP Version 12. No new evidence was added and the classification did not change.

intellectual developmental disorder, X-linked, syndromic, Siderius typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010286

Submitter: PanelApp Australia

intellectual developmental disorder, X-linked, syndromic, Siderius typeSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010286

Submitter: Orphanet

intellectual developmental disorder, X-linked, syndromic, Siderius typeDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010286

Submitter: G2P

intellectual developmental disorder, X-linked, syndromic, Siderius typeSTRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010286

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked, syndrome, Siderius typeXL

Manifestation: Craniofacial; 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

Refs: 10398231; 16199551; 17594395; 17661819; 23092983Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PHF8 variants in ClinVar

7 Conditions Cataloged
not providedTotal: 166
Inborn genetic diseasesTotal: 95
Syndromic X-linked intellectual disability Siderius typeTotal: 43
not specifiedTotal: 41
PHF8-related disorderTotal: 22
Intellectual disabilityTotal: 2
Developmental and epileptic encephalopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015107.3. 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.

EffectPLPVUSLBBSum
synonymous
12
clinvar
57
clinvar
2
clinvar
 71
missense
1
clinvar
1
clinvar
212
clinvar
18
clinvar
 232
nonsense
4
clinvar
7
clinvar
7
clinvar
 18
start loss
0
frameshift
9
clinvar
3
clinvar
1
clinvar
 13
splice donor/acceptor (+/-2bp)
1
clinvar
8
clinvar
18
clinvar
 27
Total1519250752361

Highest pathogenic variant AF is 0.00000836263

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_015107.3RefSeqNP_055922.121MANE Select
ENST00000338154.11EnsemblENSP00000338868.621MANE Select
NM_001184896.1RefSeqNP_001171825.122Standard
NM_001184897.2RefSeqNP_001171826.121Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
phf8Danio rerio

Structure: pharyngeal arch 1

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Ectoderm Differentiation
  • HDMs demethylate histones
  • Chromatin modifying enzymes
  • Condensation of Prophase Chromosomes
  • Chromatin organization

Biological Process

  • G1/S transition of mitotic cell cycle
  • brain development
  • histone H3-K9 demethylation
  • histone H4-K20 demethylation
  • positive regulation of transcription, DNA-templated

Molecular Function

  • chromatin binding
  • iron ion binding
  • protein binding
  • zinc ion binding
  • 2-oxoglutarate-dependent dioxygenase activity

Cellular Component

  • nucleus
  • nucleoplasm
  • nucleolus
  • nuclear membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000357988
Coding exons
22
Length
112283
Individuals with no LoFs
125738
Homozygous LoFs
1
Heterozygous LoFs
6
Defined
125745
p
0.0000278
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.981994310.4610.00003476924
Missense (PolyPhen)13122.650.1062206
Synonymous0.4301641710.9580.00001382097
Loss of Function5.13540.00.1250.00000323638

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000760.000062rare
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.0000720.000054rare
Finnish00.0absent
European (Non-Finnish)0.0000490.000035rare
South Asian0.0000580.000033rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Histone lysine demethylase with selectivity for the di- and monomethyl states that plays a key role cell cycle progression, rDNA transcription and brain development. Demethylates mono- and dimethylated histone H3 'Lys-9' residue (H3K9Me1 and H3K9Me2), dimethylated H3 'Lys-27' (H3K27Me2) and monomethylated histone H4 'Lys-20' residue (H4K20Me1). Acts as a transcription activator as H3K9Me1, H3K9Me2, H3K27Me2 and H4K20Me1 are epigenetic repressive marks. Involved in cell cycle progression by being required to control G1-S transition. Acts as a coactivator of rDNA transcription, by activating polymerase I (pol I) mediated transcription of rRNA genes. Required for brain development, probably by regulating expression of neuron-specific genes. Only has activity toward H4K20Me1 when nucleosome is used as a substrate and when not histone octamer is used as substrate. May also have weak activity toward dimethylated H3 'Lys-36' (H3K36Me2), however, the relevance of this result remains unsure in vivo. Specifically binds trimethylated 'Lys-4' of histone H3 (H3K4me3), affecting histone demethylase specificity: has weak activity toward H3K9Me2 in absence of H3K4me3, while it has high activity toward H3K9me2 when binding H3K4me3. {ECO:0000269|PubMed:19843542, ECO:0000269|PubMed:20023638, ECO:0000269|PubMed:20101266, ECO:0000269|PubMed:20208542, ECO:0000269|PubMed:20346720, ECO:0000269|PubMed:20421419, ECO:0000269|PubMed:20531378, ECO:0000269|PubMed:20548336, ECO:0000269|PubMed:20622853, ECO:0000269|PubMed:20622854}.;
Disease
DISEASE: Mental retardation, X-linked, syndromic, Siderius type (MRXSSD) [MIM:300263]: A syndrome characterized by mild to borderline mental retardation with or without cleft lip/cleft palate. {ECO:0000269|PubMed:16199551, ECO:0000269|PubMed:17661819, ECO:0000269|PubMed:20101266, ECO:0000269|PubMed:20208542, ECO:0000269|PubMed:20346720, ECO:0000269|PubMed:20421419, ECO:0000269|PubMed:20548336, ECO:0000269|PubMed:20622853, ECO:0000269|PubMed:20622854}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.101

Intolerance Scores

LoFtool
0.352
RVIS EVS
-0.03
RVIS percentile EVS
51.92

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.183

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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