ASXL3

protein-coding

ASXL transcriptional regulator 3

Gene summary

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]

Previous symbols:

KIAA1713

MANE transcript

NM_030632.3

Inheritance

ClinVar variants

P:267U:446B:347

Top phenotype

Bainbridge-Ropers syndrome

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chr18:33,578,219-33,751,195

External References & Databases

Ensembl (ENSG00000141431)

Transcript & Mutation Effects

hg38 • Region Span ~173.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bainbridge-Ropers syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014205

Submitter: Orphanet

Bainbridge-Ropers syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014205

Submitter: PanelApp Australia

Bainbridge-Ropers syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014205

Submitter: Labcorp Genetics (formerly Invitae)

Bainbridge-Ropers syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014205

Submitter: G2P

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

Truncating *ASXL3* variants were first reported in relation to syndromic intellectual disability (also known as Bainbridge-Ropers syndrome) in 2013 (Bainbridge et al., PMID: 23383720). Clinical features in affected individuals include feeding difficulties, hypotonia, developmental delay, limited speech, intellectual disability of variable severity, and characteristic facial features. Behavioral issues, including autism spectrum disorder or autistic traits, are common. Seizures are reported in about a third of individuals. Over 100 affected individuals with nonsense, frameshift, and splicing variants have been reported (PMID: 34436830). Most variants are *de novo* and cluster in the last and penultimate exons (PMID: 23383720). Both dominant negative (PMID: 23383720) and loss of function mechanisms (PMID: 26647312) have been proposed. Further studies are needed to understand the mechanism of disease. This gene-disease association is also supported by experimental evidence. The ASXL gene family (*ASXL1*, *ASXL2*, and *ASXL3*) participates in body patterning during embryogenesis and encodes proteins involved in epigenetic and transcriptional regulation (PMID: 23736028). Germline *de novo* truncating variants in *ASXL1* and *ASXL2* have been implicated in Bohring-Opitz and Shashi-Pena syndromes, which result in overlapping features of intellectual disability and dysmorphic features (PMIDs: 21706002, 27693232). Further support is provided by animal models in mice (doi: 10.1101/2021.07.20.452995) and frogs (PMID: 32132929). The mouse model was not formally scored in this curation, as it has yet to be published. In summary, there is definitive evidence supporting the relationship between *ASXL3* and autosomal dominant syndromic intellectual disability. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on October 6, 2021 (SOP Version 8).

Bainbridge-Ropers syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014205

Submitter: Illumina

Clinical Genomic Database (CGD)

Bainbridge-Ropers syndromeAD

Manifestation: Craniofacial; Dermatologic; 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: 23383720

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ASXL3 variants in ClinVar

29 Conditions Cataloged

not providedTotal: 545

Inborn genetic diseasesTotal: 313

Severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndromeTotal: 285

not specifiedTotal: 166

ASXL3-related disorderTotal: 118

Intellectual disabilityTotal: 16

See casesTotal: 7

Syndromic intellectual disabilityTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_030632.3. 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			8 clinvar	123 clinvar	8 clinvar	139
missense		2 clinvar	422 clinvar	204 clinvar	10 clinvar	638
nonsense	40 clinvar	42 clinvar	4 clinvar			86
start loss						0
frameshift	88 clinvar	84 clinvar	11 clinvar	1 clinvar	1 clinvar	185
splice donor/acceptor (+/-2bp)	5 clinvar	6 clinvar	1 clinvar			12
Total	133	134	446	328	19	1060

Highest pathogenic variant AF is 0.0017643699

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_030632.3	RefSeq	NP_085135.1	12	MANE Select
ENST00000269197.12	Ensembl	ENSP00000269197.4	12	MANE Select
ENST00000592288.6	Ensembl	ENSP00000465053.1	10	Standard
ENST00000592541.6	Ensembl	ENSP00000466655.2	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

transcription, DNA-templated
animal organ morphogenesis
positive regulation of transcription by RNA polymerase II

Molecular Function

DNA binding
chromatin binding
peroxisome proliferator activated receptor binding
metal ion binding

Cellular Component

nuclear chromatin
nucleus
PR-DUB complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000269197
Coding exons: 12
Length: 172578
Individuals with no LoFs: 124624
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 124638
p: 0.0000562

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.607	1097	1.16e+3	0.950	0.0000588	14607
Missense (PolyPhen)		296	369.71	0.80062		4842
Synonymous	-0.125	448	445	1.01	0.0000251	4534
Loss of Function	7.02	8	72.6	0.110	0.00000386	993

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000065	0.000065	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000056	rare
Finnish	0.000093	0.000093	rare
European (Non-Finnish)	0.000063	0.000062	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Putative Polycomb group (PcG) protein. PcG proteins act by forming multiprotein complexes, which are required to maintain the transcriptionally repressive state of homeotic genes throughout development. PcG proteins are not required to initiate repression, but to maintain it during later stages of development. They probably act via methylation of histones, rendering chromatin heritably changed in its expressibility (By similarity). {ECO:0000250}.;

Intolerance Scores

LoFtool: 0.222
RVIS EVS: -0.67
RVIS percentile EVS: 15.87

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.254

Gene Damage Prediction

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