PHC1

protein-coding

polyhomeotic homolog 1, the group of Sterile alpha motif domain containing

Gene summary

This gene is a homolog of the Drosophila polyhomeotic gene, which is a member of the Polycomb group of genes. The gene product is a component of a multimeric protein complex that contains EDR2 and the vertebrate Polycomb protein BMH1. The gene product, the EDR2 protein, and the Drosophila polyhomeotic protein share 2 highly conserved domains, named homology domains I and II. These domains are involved in protein-protein interactions and may mediate heterodimerization of the protein encoded by this gene and the EDR2 protein. [provided by RefSeq, Jul 2008]

Previous symbols:

EDR1

MANE transcript

NM_004426.3

Inheritance

ClinVar variants

P:3U:146B:25

Top phenotype

Microcephaly 11, primary, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.12

Max pathogenic AF

—

Genomic locus

chr12:8,913,896-8,941,467

External References & Databases

Ensembl (ENSG00000111752)

Transcript & Mutation Effects

hg38 • Region Span ~27.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly 11, primary, autosomal recessiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014173

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive primary microcephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: Orphanet

microcephaly 11, primary, autosomal recessiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014173

Submitter: G2P

microcephaly 11, primary, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014173

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Microcephaly 11, primary, autosomal recessiveAR

Manifestation: 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: 23418308

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PHC1 variants in ClinVar

7 Conditions Cataloged

not specifiedTotal: 158

not providedTotal: 20

PHC1-related disorderTotal: 13

Microcephaly 11, primary, autosomal recessiveTotal: 5

Primary microcephalyTotal: 1

Intellectual disabilityTotal: 1

PHC1-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004426.3. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	18 clinvar		19
missense		1 clinvar	144 clinvar	5 clinvar	1 clinvar	151
nonsense	1 clinvar			1 clinvar		2
start loss						0
frameshift		1 clinvar				1
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	2	146	24	1	174

Highest pathogenic variant AF is 0.000001422196

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 175 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004426.3	RefSeq	NP_004417.2	14	MANE Select
ENST00000544916.6	Ensembl	ENSP00000437659.1	14	MANE Select
NM_001413738.1	RefSeq	NP_001400667.1	14	Standard
NM_001413739.1	RefSeq	NP_001400668.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signal Transduction
Gene expression (Transcription)
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known
the prc2 complex sets long-term gene silencing through modification of histone tails
Transcriptional Regulation by E2F6

Biological Process

multicellular organism development
histone ubiquitination
negative regulation of G0 to G1 transition

Molecular Function

DNA binding
protein binding
zinc ion binding

Cellular Component

nucleus
nucleoplasm
PcG protein complex
PRC1 complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000543824
Coding exons: 14
Length: 27572
Individuals with no LoFs: 125744
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125748
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.92	375	495	0.757	0.0000266	6373
Missense (PolyPhen)		85	112.03	0.7587		1396
Synonymous	-0.115	191	189	1.01	0.0000101	2071
Loss of Function	5.40	5	43.4	0.115	0.00000207	485

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of a Polycomb group (PcG) multiprotein PRC1- like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility. Required for proper control of cellular levels of GMNN expression. {ECO:0000269|PubMed:23418308}.;
Disease: DISEASE: Microcephaly 11, primary, autosomal recessive (MCPH11) [MIM:615414]: A form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age- related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. {ECO:0000269|PubMed:23418308}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.147

Intolerance Scores

LoFtool: 0.395
RVIS EVS: 0.05
RVIS percentile EVS: 57.48

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.745

Gene Damage Prediction

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