• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
PHF21A (HGNC:24156) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
PHD finger protein 21A
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
No previous names found
Alias symbols
BHC80, KIAA1696, BM-006
%HI
2.85(Read more about the DECIPHER Haploinsufficiency Index)
pLI
1(Read more about gnomAD pLI score)
LOEUF
0.08(Read more about gnomAD LOEUF score)
Cytoband
11p11.2
Genomic Coordinates
GRCh37/hg19: chr11:45950870-46143005 NCBI Ensembl UCSC
GRCh38/hg38: chr11:45929319-46121454 NCBI Ensembl UCSC
MANE Select Transcript
NM_001352027.3 ENST00000676320.1 (Read more about MANE Select)
Function
Component of the BHC complex, a corepressor complex that represses transcription of neuron-specific genes in non-neuronal cells. The BHC complex is recruited at RE1/NRSE sites by REST and acts by deacetylating and demethylating specific sites on histones, thereby acting as a chromatin modifier. In the BHC complex, it may act as a scaffold. Inhibits KDM1A-mediated demethylation of 'Lys-4' of histone H3 in vitro, suggesting a role in demethylation regulation. {ECO:0000269|PubMed:16140033}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-20562
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
09/21/2023

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • Complex Neurodevelopmental Disorder Monarch
HI Evidence:
  • PUBMED: 30487643
    Hamanaka et al. (2019) identified three de novo truncating variants within the PHF21A gene resulting in PHF21A haploinsufficiency using trio-based exome sequencing. The common features in the three cases included intellectual disability, motor development delay, speech delay and craniofacial anomalies. The variants in case 1 [c.1220dupC, p.(Glu408Argfs*3)] and case 3[c.657_658insAA, p.(Pro220Asnfs*48)] are likely to be functionally null. The variant in case 2 [c.1738C>T, p.(Arg580*)] is located in the penultimate exon and could form a truncating protein without the C terminal coiled-coiled domain. Given the PHF21A functions as a subunit of a protein complex, the truncating PHF21A protein in case 3 may not be incorporated into the protein complex leading to functional impairment. A subsequent publication (Kim et al. 2019, PMID:31649809) reports this variant (de novo) in 2 additional probands with neurodevelopmental disorders. Kim et al. note that this particular variant is predicted to remove the LZD2 functional domain.
  • PUBMED: 36555772
    Butera et al. (2022) identified a truncating variant in PHF21A that would be predicted to result in nonsense mediated decay of the protein (c.649_650del/p.Gln217Valfs*6) in a 16 year old male individual with global developmental delay, seizures with onset at age 13, microcephaly, micrognathia, hypotonia, joint laxity, and scoliosis. The variant was found to be inherited from the individual's healthy father, who was found to have mosaicism with the variant present in 5% of blood cells.
  • PUBMED: 36158052
    Lee et al, (2022) identified a de novo nonsense variant in PHF21A that would be predicted to result in nonsense mediated decay of the protein (c.1171A>T/p.Lys391*) in a 26 year old female individual with developmental delay and severe intellectual disability who also had behavioral abnormalities, seizures beginning at age 12, mild hypotonia, mild craniofacial dysmorphism, and overgrowth.
  • PUBMED: 31981491
    Satterstrom et al, (2020) performed WES on 11,986 individuals with autism. Two de novo predicted loss of function variants in PHF21A, c.1153delA/p.Ser385Alafs*30 and c.840delC/p.Ile281Serfs*14, were identified in affected individuals.
  • PUBMED: 25363760
    De Rubeis et al, (2014) performed WES on 9937 individuals with autism and their parental controls. One de novo predicted loss of function variant in PHF21A, c.976_979delAAGC/p.Lys326Glnfs*47, was identified in an affected female.
  • PUBMED: 35982159
    Zhou et al, (2022) reviewed WES results for 42,607 individuals with autism, some that had been previously published, but including 35,130 from a cohort that had not. In this group, 5 de novo variants were found in PHF21A. Of these, three had not previously been published. One was in the final exon of the gene, c.1959del/p.Ala654Profs*103, and would result in an elongated protein product. One was a nonsense variant that would be predicted to lead to nonsense mediated decay of the resulting protein, c.1171C>T/p.Arg391*. The last was a variant affecting the canonical splice region of exon 12, predicted to result in loss of a donor splice site, c.1147+2del.
HI Evidence Comments:
PHF21A is one of three genes that is involved in the contiguous gene deletion syndrome Potocki-Shaffer syndrome (PSS), characterized by developmental delay, intellectual disability, multiple exostoses, and parietal foramina. Loss of the gene EXT2 causes the multiple exostoses phenotype, while loss of ALX4 causes the parietal foramina phenotype. Loss of PHF21A within this contiguous deletion syndrome has been proposed as a cause for the neurodevelopmental phenotype. Single nucleotide variants as well as small insertions and deletions affecting only the PHF21A gene have been reported in association with intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism, with or without seizures (MIM:618725). A variable but consistent phenotype has been described in individuals with truncating variants that would be predicted to undergo nonsense-mediated decay (PMID:30487643; PMID: 36158052; PMID:36555772; PMID:33875846). Of note, all reported individuals for whom parental studies have been possible have had de novo findings, except for one, whose unaffected father was found to have low level mosaicism (5%) for the variant (PMID:36555772). In addition to those variants that, due to their terminating effect early in the gene, are predicted to result in nonsense mediated decay, several variants predicted to affect splicing as well as frameshifting variants affecting the penultimate and final exons of the gene have also been described (PMID:31649809; PMID:30487643; PMID:25262651; PMID:36158052; PMID:35982159). Kim et al (PMID:31649809) reported the identification of a C-terminal domain composed of an intrinsically disordered region that they propose to be critical to the protein function, though functional studies are required to confirm this. Additionally, de novo predicted loss of function variants in PHF21A have been reported as part of large autism cohort studies (PMID:25363768; PMID:31981491; PMID:25363760; PMID: 35982159), again providing evidence that loss of function of PHF21A is responsible for a neurodevelopmental phenotype. Further evidence to support haploinsufficiency of PHF21A in association with neurodevelopmental and craniofacial anomalies is provided by Bertoli-Avella et al (PMID:33875846), who identified a heterozygous de novo frameshifting variant (c.976-979delAAGC, p.Lys326fs) in an individual with global developmental delay and craniofacial features, as well as Kim et al (PMID:22770980), who identified two individuals and characterized a third with de novo apparently balanced translocations containing breakpoints within PHF21A. Functional studies performed by the group demonstrated functional consequences of PHF21A haploinsufficiency on transcriptional regulation and provided evidence of PHF21A's involvement in craniofacial and neuronal development in model organisms.

Triplosensitivity (TS) Score Details

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

Genomic View

Select assembly: (NC_000011.9) (NC_000011.10)