• 3
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
PHIP (HGNC:15673) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
pleckstrin homology domain interacting protein
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
WDR11
Alias symbols
ndrp, FLJ20705, DCAF14, BRWD2
%HI
12.52(Read more about the DECIPHER Haploinsufficiency Index)
pLI
1(Read more about gnomAD pLI score)
LOEUF
0.11(Read more about gnomAD LOEUF score)
Cytoband
6q14.1
Genomic Coordinates
GRCh37/hg19: chr6:79644136-79787971 NCBI Ensembl UCSC
GRCh38/hg38: chr6:78934419-79078254 NCBI Ensembl UCSC
MANE Select Transcript
NM_017934.7 ENST00000275034.5 (Read more about MANE Select)
Function
Probable regulator of the insulin and insulin-like growth factor signaling pathways. Stimulates cell proliferation through regulation of cyclin transcription and has an anti-apoptotic activity through AKT1 phosphorylation and activation. Plays a role in the regulation of cell morphology and cytoskeletal organization. {ECO:0000269|PubMed:12242307, ECO:0000269|PubMed:21834987}. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-29353
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Sufficient Evidence for Haploinsufficiency (3)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Last Evaluated:
04/13/2022

Haploinsufficiency (HI) Score Details

HI Score:
3
HI Evidence Strength:
Sufficient Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • Chung-Jansen syndrome; CHUJANS Monarch
HI Evidence:
  • PUBMED: 23033978
    de Ligt et al (NEJM, 2012) performed family-based diagnostic exome sequencing to evaluate role of de novo as well as X linked inherited variants among 100 patients with unexplained intellectual disability (including unaffected parents). All patients had undergone genomic microarray (250K Affymetrix SNP array) as well as targeted gene tests, with metabolic screening, however these evaluations did not lead to a diagnosis. One nonsense de novo mutation in exon 30 of 42 of PHIP Chr6(GRCh37):g.79672902A>C; PHIP:c.3447T>G; p.(Tyr1149*), was identified in a girl (ID in paper: trio 5) with developmental delay and facial dysmorphism, however MRI of the brain showed no abnormalities. Of the three categories of genes cataloged in this paper, known intellectual-disability (ID) genes, novel ID genes, and candidate ID genes; the mutation in PHIP fell into the last category (Table S3, S10). The authors assert that this is not a known ID gene, similar nonsense mutations in this gene have not been reported, and the mutational change is not at an evolutionary conserved genomic base (Table S3). Although the mRNA produced might be targeted for nonsense mediated decay, no additional functional studies were performed by the authors. At the time of submission by the authors in ClinVar, the p.(Tyr1149*) change has been listed as a variant of uncertain significance (submission ID: SCV000056894).
  • PUBMED: 27900362
    Webster et al (Cold Spring Harb Mol Case Stud 2016) studied 2522 patient with developmental delay or intellectual disability using whole exome sequencing. The authors identified two patients with novel de novo heterozygous variants in PHIP. These included a frameshift deletion NM_017934.6(PHIP):c.779del; p.Leu260Trpfs*48 in exon 8 and a missense variant NM_017934.6(PHIP):c.50T>C; p.Phe17Ser in exon 2 in two unrelated individuals. Both patients are girls with overlapping phenotypes similar to the previously reported patient with a de novo heterozygous nonsense mutation in PHIP, p.Y1149* (PMID 1: 23033978). This included developmental delay, intellectual disability, anxiety, hypotonia, obesity, and dysmorphic facial features. No brain malformations were observed. Neither variant was observed in ExAC and in silco tools predicted conflicting effects of pathogenicity for the highly conserved missense, p.F17S, variant (tolerant by SIFT and disease causing by MutationTaster). Of note, the patient with the missense variant also had an additional genetic variant reported as a 95-kb paternally inherited 5q23.2 duplication, including CEP120 and CSNK1G3 genes. Overall the authors point out that PHIP has a high haploinsufficiency score [p(HI) = 0.95], albeit based on a predictive model (PMID: 20976243) and is also intolerant to loss-of-function variants [(p(LI) = 1.00]. Both variants were reported in ClinVar as likely pathogenic (accession ID: SCV000282078 for the frameshift and SCV000282077 for the missense -- assertion method based on GeneDx variant classification guidelines).
  • PUBMED: 34773373
    Dietrich at el (2021) conducted a systematic literature review of all 35 reported patients (including those from Craddock et al., 2019; Jansen et al., 2018; Lee & Zhou, 2007). To date, all variants are unique, but their additional patient has a 5bp deletion leading to frameshift at the same protein position as a previous report.
  • PUBMED: 29209020
    Jansen et al (2018) used a genotype first approach to identify a subset of 5 patients with loss of function PHIP variants from a large cohort of patients with intellectual disability. Phenotypic assessment indicated the 5 were more similar to each other than by chance. They then identified a further 17 patients via collaboration. The majority of patients had obesity (74%), intellectual disability (78%) and behavioural problems (78%). Five of the 23 had loss of function variants. All patients for whom trio testing could be completed were found to be de novo, except for two affected sibs who inherited their pathogenic variant from their affected father. They also identified the first two reported patients (individuals 12 and 14) who had haploinsufficiency (confirmed by RT-qPCR) resulting from a de novo disruptive balanced translocation and a de novo whole gene deletion.
  • PUBMED: 33004838
    Wang et al. 2020 performed targeted sequencing on 125 genes in a cohort of over 16,000 individuals with neurodevelopmental disorder (NDD). Authors identified 10 likely gene-disruptive (LGD) variants (either a frameshift, nonsense, or canonical splice donor/acceptor variant) in PHIP and found the mutation burden test for LGD variants to have a p-value of .00796.
HI Evidence Comments:
Loss of function variants (defined as stop-gain, frameshift, canonical splice site variants predicted to result in reduced protein product and whole gene deletions) in PHIP have been linked to Chung-Jansen syndrome. One of the most comprehensive studies (Jansen et al. 2018) undertook gene expression studies to confirm decreased expression in two patients with a whole gene deletion and a disruptive balanced translocation.

Triplosensitivity (TS) Score Details

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

Genomic View

Select assembly: (NC_000006.11) (NC_000006.12)