ASXL3

Chr 18AD

ASXL transcriptional regulator 3

Also known as: BRPS, KIAA1713

NCBI Gene: 80816 ENSG00000141431 UniProt: Q9C0F0 OMIM: 615115

The protein contains a PHD zinc finger domain and regulates gene transcription by binding to and inhibiting nuclear hormone receptors LXRalpha and TRbeta, and may also inhibit histone deubiquitination. Mutations cause Bainbridge-Ropers syndrome, an autosomal dominant condition characterized by feeding difficulties and developmental delay. The gene is highly intolerant to loss-of-function variants, and mutations predominantly cause disease through haploinsufficiency.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein containing a plant homeodomain (PHD) zinc finger domain that plays a role in the regulation of gene transcription. The encoded protein has been shown to negatively regulate lipogenesis by binding to and inhibiting the transcriptional activity of two nuclear hormone receptors, oxysterols receptor LXR-alpha (LXRalpha) and thyroid hormone receptor beta (TRbeta). The encoded protein may also inhibit histone deubiquitination. Mutations in this gene have been identified in human patients with Bainbridge-Ropers syndrome, which is characterized by feeding difficulties, developmental delay and other features. [provided by RefSeq, May 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.201 OMIM phenotype

Clinical Summary— ASXL3

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Gene-Disease Validity (ClinGen)

syndromic intellectual disability · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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.

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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GeneReview available — ASXL3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.20LOEUF

pLI 1.000

Z-score 7.02

OE 0.11 (0.06–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.61Z-score

OE missense 0.95 (0.90–1.00)

1097 obs / 1155.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.11 (0.06–0.20)

0≤0.351.4

Missense OE?0.95 (0.90–1.00)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 8 / 72.6Missense obs/exp: 1097 / 1155.1Syn Z: -0.12

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongASXL3-related Bainbridge-Ropers syndromeLOFAD

This gene — mechanism propensity

0.2299th %ile

GOF

0.2298th %ile

LOF

0.81top 5%

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

LOFprediction above median · 1 literature citation · LOEUF 0.20 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFDe novo dominant ASXL3 mutations alter H2A deubiquitination and transcription in Bainbridge-Ropers syndrome1

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

References