GeneBe

ASXL1

protein-coding

ASXL transcriptional regulator 1

Gene summary

This gene is similar to the Drosophila additional sex combs gene, which encodes a chromatin-binding protein required for normal determination of segment identity in the developing embryo. The protein is a member of the Polycomb group of proteins, which are necessary for the maintenance of stable repression of homeotic and other loci. The protein is thought to disrupt chromatin in localized areas, enhancing transcription of certain genes while repressing the transcription of other genes. The protein encoded by this gene functions as a ligand-dependent co-activator for retinoic acid receptor in cooperation with nuclear receptor coactivator 1. Mutations in this gene are associated with myelodysplastic syndromes and chronic myelomonocytic leukemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

MANE transcript

NM_015338.6

Inheritance

AD

ClinVar variants

P:165U:1465B:1188

Top phenotype

Bohring-Opitz syndrome

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr20:32,358,330-32,439,319

External References & Databases

Ensembl (ENSG00000171456)NCBI Gene (171023)OMIM (612990)HGNC:18318GenCCUniProt (Q8IXJ9)AlphaFoldClinVar (ASXL1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~81.0 kb
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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bohring-Opitz syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011510

Submitter: PanelApp Australia

Bohring-Opitz syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011510

Submitter: Illumina

Bohring-Opitz syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011510

Submitter: Labcorp Genetics (formerly Invitae)

Bohring-Opitz syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011510

Submitter: Orphanet

Bohring-Opitz syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011510

Submitter: G2P

Bohring-Opitz syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011510

Submitter: ClinGen

​​Truncating ASXL1 variants were first reported in relation to autosomal dominant Bohring-Opitz syndrome in 2011 (Hoischen et al., PMID: 21706002). ASXL1 encodes a chromatin binding protein involved in transcriptional regulation. Bohring-Opitz syndrome is characterized by intrauterine growth restriction, feeding difficulties, developmental delay/intellectual disability, and distinctive dysmorphic facial features, and posture. The mechanism of pathogenicity is loss of function. At least 27 unique variants (nonsense and frameshift) have been reported in 34 probands in 14 publications (PMIDs: 21706002, 25921057, 33529703, 28229513, 30147881, 31692235, 22419483, 31819025, 29681100, 26364555, 27043953, 29681105, 31969346, 30806792) included in this curation. Variants are de novo in most probands though inheritance from a mosaic parent has been reported (PMIDs: 29681100, 33751773). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Acquired somatic mosaicism of ASXL1 variants, including variants noted in individuals with Bohring-Opitz syndrome, can occur with aging in healthy individuals during hematopoietic clonal expansion (PMID: 28229513). This explains the presence of a large number of cases with somatic truncating variants in population databases such as gnomAD. 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 ASXL2 and ASXL3 have been implicated in Shashi-Pena and Bainbridge-Ropers syndromes, which result in overlapping features of intellectual disability and dysmorphic features (PMIDs: 27693232, 23383720). In summary, ASXL1 is definitively associated with autosomal dominant Bohring-Opitz syndrome. This classification was approved by the Intellectual Disability and Autism Gene Curation Expert Panel on 07/30/2021 (SOP Version 8).

Bohring-Opitz syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011510

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

Bohring-Opitz 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: 21706002; 22419483Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ASXL1 variants in ClinVar

36 Conditions Cataloged
Inborn genetic diseasesTotal: 2180
not providedTotal: 1094
Bohring-Opitz syndromeTotal: 173
not specifiedTotal: 119
ASXL1-related disorderTotal: 92
Myelodysplastic syndromeTotal: 21
Myeloproliferative neoplasmTotal: 11
Intellectual disabilityTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015338.6. 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.

EffectPLPVUSLBBSum
synonymous
2
clinvar
841
clinvar
4
clinvar
 847
missense
1
clinvar
2
clinvar
1444
clinvar
325
clinvar
18
clinvar
 1790
nonsense
36
clinvar
21
clinvar
5
clinvar
 62
start loss
2
clinvar
 2
frameshift
61
clinvar
36
clinvar
11
clinvar
 108
splice donor/acceptor (+/-2bp)
5
clinvar
3
clinvar
1
clinvar
 9
Total1036214651166222818

Highest pathogenic variant AF is 0.00042764976

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_015338.6RefSeqNP_056153.213MANE Select
ENST00000375687.10EnsemblENSP00000364839.413MANE Select
NM_001164603.1RefSeqNP_001158075.15Standard
NM_001363734.1RefSeqNP_001350663.112Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Post-translational protein modification
  • Metabolism of proteins
  • UCH proteinases
  • Deubiquitination

Biological Process

  • cell morphogenesis
  • heart morphogenesis
  • transcription, DNA-templated
  • animal organ morphogenesis
  • protein deubiquitination

Molecular Function

  • DNA binding
  • chromatin binding
  • transcription coactivator activity
  • protein binding
  • retinoic acid receptor binding

Cellular Component

  • nuclear chromatin
  • nucleus
  • nucleoplasm
  • PR-DUB complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000375687
Coding exons
13
Length
80968
Individuals with no LoFs
125652
Homozygous LoFs
0
Heterozygous LoFs
96
Defined
125748
p
0.000382
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.6367918430.9380.000050110006
Missense (PolyPhen)230297.050.774293532
Synonymous-0.4163493391.030.00002123221
Loss of Function2.773152.70.5890.00000322616

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American0.000170.00017rare
Ashkenazi Jewish0.000600.00060rare
East Asian0.000230.00022rare
Finnish0.000180.00018rare
European (Non-Finnish)0.000600.00059rare
South Asian0.000200.00013rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Probable Polycomb group (PcG) protein involved in transcriptional regulation mediated by ligand-bound nuclear hormone receptors, such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor gamma (PPARG). Acts as coactivator of RARA and RXRA through association with NCOA1. Acts as corepressor for PPARG and suppresses its adipocyte differentiation-inducing activity (By similarity). Non-catalytic component of the PR-DUB complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at 'Lys-119' (H2AK119ub1). {ECO:0000250, ECO:0000269|PubMed:16606617, ECO:0000269|PubMed:20436459}.;
Disease
DISEASE: Bohring-Opitz syndrome (BOPS) [MIM:605039]: A syndrome characterized by severe intrauterine growth retardation, poor feeding, profound mental retardation, trigonocephaly, prominent metopic suture, exophthalmos, nevus flammeus of the face, upslanting palpebral fissures, hirsutism, and flexion of the elbows and wrists with deviation of the wrists and metacarpophalangeal joints. {ECO:0000269|PubMed:21706002}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Myelodysplastic syndrome (MDS) [MIM:614286]: A heterogeneous group of closely related clonal hematopoietic disorders. All are characterized by a hypercellular or hypocellular bone marrow with impaired morphology and maturation, dysplasia of the myeloid, megakaryocytic and/or erythroid lineages, and peripheral blood cytopenias resulting from ineffective blood cell production. Included diseases are: refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), refractory cytopenia with multilineage dysplasia and ringed sideroblasts (RCMD-RS); chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative disease. MDS is considered a premalignant condition in a subgroup of patients that often progresses to acute myeloid leukemia (AML). {ECO:0000269|PubMed:19388938, ECO:0000269|PubMed:20182461}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.0787

Intolerance Scores

LoFtool
0.955
RVIS EVS
0.17
RVIS percentile EVS
65.77

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.756

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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