PHF21A

Chr 11AD

PHD finger protein 21A

Also known as: BHC80, BM-006, IDDBCS, NEDMS

NCBI Gene: 51317 ENSG00000135365 UniProt: Q96BD5 OMIM: 608325

The protein BHC80 functions as a component of a BRAF35/histone deacetylase complex that represses neuron-specific genes through the repressor element-1 (RE1) regulatory sequence. Loss-of-function mutations cause autosomal dominant intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures. The gene is highly intolerant to loss-of-function variants, indicating haploinsufficiency as the likely disease mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.081 OMIM phenotype

Clinical Summary— PHF21A

🧬

Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

💊

Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.08LOEUF

pLI 1.000

Z-score 5.64

OE 0.00 (0.00–0.08)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.86Z-score

OE missense 0.59 (0.53–0.66)

223 obs / 379.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.08)

0≤0.351.4

Missense OE?0.59 (0.53–0.66)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 0 / 37.1Missense obs/exp: 223 / 379.9Syn Z: 1.17

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPHF21A-related Potocki-Shaffer syndromeLOFAD

This gene — mechanism propensity

0.2598th %ile

GOF

0.2198th %ile

LOF

0.86top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.08 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFAs the chromosomal deletion does not encompass PHF21A, this case lends further support that haploinsufficiency of PHF21A contributes to the intellectual disability and craniofacial abnormalities in PSS and that there are other genes in the region which likely contribute to the behavioral phenotype i1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References