PHF21A

protein-coding

PHD finger protein 21A, the group of PHD finger proteins

Gene summary

The PHF21A gene encodes BHC80, a component of a BRAF35 (MIM 605535)/histone deacetylase (HDAC; see MIM 601241) complex (BHC) that mediates repression of neuron-specific genes through the cis-regulatory element known as repressor element-1 (RE1) or neural restrictive silencer (NRS) (Hakimi et al., 2002 [PubMed 12032298]).[supplied by OMIM, Nov 2010]

MANE transcript

NM_001352027.3

Inheritance

ClinVar variants

P:48U:171B:119

Top phenotype

Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr11:45,929,319-46,121,454

External References & Databases

Ensembl (ENSG00000135365)

Transcript & Mutation Effects

hg38 • Region Span ~192.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Potocki-Shaffer syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011022

Submitter: G2P

intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032883

Submitter: Labcorp Genetics (formerly Invitae)

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

*PHF21A* variants were first reported in relation to complex neurodevelopmental disorder in 2019 (PMID:30487643). The *PHF21A* gene encodes BHC80, a component of the BRAF35/HDAC complex that mediates repression of neuron-specific genes. At least 10 variants in *PHF21A*, including nonsense, frameshift and missense variants have been reported in the literature, with most variants occurring de novo. Patients with variants in this gene have been reported to have developmental delay, intellectual disability, and facial dysmorphism. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 2 publications (PMID: 30487643 and 31649809), including 6 frameshift, 3 nonsense (recurrent - c.1738C>T) and 1 missense (AT Hook region) (12 pts). Three of the frameshift variants are located at the last exons and are predicted to elongate the transcription product (PMID: 31649809). Due to limitations of the scoring interface, variants in two probands are not able to be formally entered. Patient 5 carries NM_001101802.1:c.1471_1472insT(p.Cys491LeufsTer?) and patient 7 carries NM_001101802.1:c.2024del(p.Gln675ArgfsTer?)) (PMID: 31649809). This gene-disease relationship is also supported by a zebrafish model that recapitulates some of the human disease phenotype (PMID:22770980) and a protein interaction study (PMID:12032298). In summary, there is definitive evidence to support the gene-disease relationship between *PHF21A* and complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 6, 2022 (SOP Version 8).

intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizuresMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032883

Submitter: Ambry Genetics

intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizuresSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032883

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizuresAD

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: 30487643; 31649809

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PHF21A variants in ClinVar

8 Conditions Cataloged

not providedTotal: 314

Inborn genetic diseasesTotal: 71

Intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizuresTotal: 44

PHF21A-related disorderTotal: 26

not specifiedTotal: 18

See casesTotal: 3

Autism spectrum disorderTotal: 1

Intellectual disabilityTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001352027.3. 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			4 clinvar	67 clinvar	7 clinvar	78
missense	1 clinvar		158 clinvar	29 clinvar	15 clinvar	203
nonsense	10 clinvar	4 clinvar				14
start loss						0
frameshift	16 clinvar	9 clinvar	2 clinvar			27
splice donor/acceptor (+/-2bp)		8 clinvar	7 clinvar	1 clinvar		16
Total	27	21	171	97	22	338

Highest pathogenic variant AF is 0.000004794389

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 139 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001352027.3	RefSeq	NP_001338956.1	16	MANE Select
ENST00000676320.1	Ensembl	ENSP00000502222.1	16	MANE Select
NM_001101802.3	RefSeq	NP_001095272.1	16	Standard
NM_001352025.3	RefSeq	NP_001338954.1	16	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
phf21ab	Danio rerio	Structure: aortic arch Quality: hypoplastic abnormal

Gene / Model

Organism

Observed Phenotype

phf21ab

Danio rerio

Structure: aortic arch

Quality: hypoplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Factors involved in megakaryocyte development and platelet production
HDACs deacetylate histones
Chromatin modifying enzymes
Hemostasis
Chromatin organization

Biological Process

negative regulation of transcription by RNA polymerase II
blood coagulation
histone deacetylation

Molecular Function

DNA binding
chromatin binding
histone deacetylase activity
protein binding
metal ion binding

Cellular Component

histone deacetylase complex
nucleoplasm
DNA repair complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000418153
Coding exons: 16
Length: 192115
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.86	223	380	0.587	0.0000201	4444
Missense (PolyPhen)		68	153.12	0.44411		1865
Synonymous	1.17	124	142	0.875	0.00000789	1366
Loss of Function	5.64	0	37.1	0.00	0.00000192	395

Population LoF Frequency

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

dbNSFP Gene Annotations

Source: dbNSFP

Function: 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}.;

Recessive Scores

pRec: 0.131

Intolerance Scores

LoFtool: 0.0517
RVIS EVS: -0.62
RVIS percentile EVS: 17.31

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.801

Gene Damage Prediction

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