PHIP

protein-coding

pleckstrin homology domain interacting protein, the group of DDB1 and CUL4 associated factors|WD repeat domain containing|Bromodomain containing

Gene summary

This gene encodes a protein that binds to the insulin receptor substrate 1 protein and regulates glucose transporter translocation in skeletal muscle cells. The encoded protein may also regulate growth and survival of pancreatic beta cells. Elevated copy number of this gene may be associated with melanoma severity and the encoded protein may promote melanoma metastasis in human patients. [provided by RefSeq, Oct 2016]

Previous symbols:

WDR11

MANE transcript

NM_017934.7

Inheritance

ClinVar variants

P:202U:632B:377

Top phenotype

Chung-Jansen synrome (Developmental delay, intellectual disability, obesity, and dysmorphic features)

gnomAD constraint

pLI —, LoF o/e 0.06

Max pathogenic AF

—

Genomic locus

chr6:78,934,419-79,078,287

External References & Databases

Ensembl (ENSG00000146247)

Transcript & Mutation Effects

hg38 • Region Span ~143.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

developmental delay, intellectual disability, obesity, and dysmorphic featuresDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0060712

Submitter: Ambry Genetics

PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0035133

Submitter: PanelApp Australia

PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0035133

Submitter: ClinGen

The *PHIP* gene is located on chromosome 6q14.1 and encodes two-protein isoforms, PHIP/DCAF14 and NDRP. It was first reported in relation to autosomal dominant PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome in 2016 (Webster et al., 2016 PMID: 27900362). The most common features in individuals with *PHIP* variants include intellectual disability, overgrowth, behavioral problems, facial dysmorphism (high forehead, full eyebrows and/or snynophrys, large ears, upturned nose and/or thick alae nasi), and other features including visual problems, tapering fingers, clinodactyly fifth fingers, gastrointestinal problems. *PHIP* has been associated with the following disease entities: AD Chung-Jansen syndrome (MIM:617991, ORPHA:589905 ) and AD PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome (MONDO:0035133, ORPHA:589905). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome. The mechanism of pathogenicity is reported to be haploinsufficiency. Analysis suggests haploinsufficiency of PHIP/DCAF14, but not NDRP, is causative of the observed phenotype. At least 11 variants (4 missense and 7 nonsense/frameshift) that have been reported in 12 probands in 2 publications (PMIDs:29209020, 31167805 ) are included in this curation. Affected individuals typically harbor de novo, heterozygous loss-of-function and missense variants (PMID: 34773373). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, there is definitive evidence to support the relationship between *PHIP* and autosomal dominant PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features 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 April 19, 2022 (SOP version 8).

PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0035133

Submitter: Labcorp Genetics (formerly Invitae)

PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0035133

Submitter: G2P

PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0035133

Submitter: Orphanet

Clinical Genomic Database (CGD)

Chung-Jansen synrome (Developmental delay, intellectual disability, obesity, and dysmorphic features)AD

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: 23033978; 27900362; 29209020

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PHIP variants in ClinVar

17 Conditions Cataloged

not providedTotal: 912

PHIP-related disorderTotal: 584

PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndromeTotal: 194

Inborn genetic diseasesTotal: 158

not specifiedTotal: 59

Early onset severe obesityTotal: 9

See casesTotal: 6

Intellectual disabilityTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017934.7. 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 clinvar	14 clinvar	271 clinvar	13 clinvar	299
missense	2 clinvar	36 clinvar	586 clinvar	82 clinvar	11 clinvar	717
nonsense	29 clinvar	33 clinvar	8 clinvar			70
start loss	1 clinvar		2 clinvar			3
frameshift	39 clinvar	25 clinvar	6 clinvar			70
splice donor/acceptor (+/-2bp)	8 clinvar	28 clinvar	16 clinvar			52
Total	79	123	632	353	24	1211

Highest pathogenic variant AF is 0.00048625233

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017934.7	RefSeq	NP_060404.4	40	MANE Select
ENST00000275034.5	Ensembl	ENSP00000275034.3	40	MANE Select
ENST00000700012.1	Ensembl	ENSP00000514753.1	18	Standard
ENST00000700013.1	Ensembl	ENSP00000514754.1	41	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of protein phosphorylation
regulation of transcription by RNA polymerase II
cytoskeleton organization
positive regulation of cell population proliferation
insulin receptor signaling pathway

Molecular Function

insulin receptor binding
protein binding
lysine-acetylated histone binding

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000275034
Coding exons: 40
Length: 142370
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 12
Defined: 125744
p: 0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.14	508	955	0.532	0.0000497	11924
Missense (PolyPhen)		162	471.6	0.34351		5877
Synonymous	0.297	308	315	0.979	0.0000158	3388
Loss of Function	8.93	6	105	0.0574	0.00000608	1255

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000072	0.000070	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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}.;

Recessive Scores

pRec: 0.106

Intolerance Scores

LoFtool: 0.444
RVIS EVS: -1.24
RVIS percentile EVS: 5.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.652

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium