MSL3
protein-codingMSL complex subunit 3, the group of MSL histone acetyltransferase complex
Gene summary
This gene encodes a nuclear protein that is similar to the product of the Drosophila male-specific lethal-3 gene. The Drosophila protein plays a critical role in a dosage-compensation pathway, which equalizes X-linked gene expression in males and females. Thus, the human protein is thought to play a similar function in chromatin remodeling and transcriptional regulation, and it has been found as part of a complex that is responsible for histone H4 lysine-16 acetylation. This gene can undergo X inactivation. Alternative splicing results in multiple transcript variants. Related pseudogenes have been identified on chromosomes 2, 7 and 8. [provided by RefSeq, Jul 2010]
- MSL3L1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~17.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0026730
Submitter: G2P
Inheritance Pattern: XL
Disease ID:MONDO:0026730
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0026730
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0026730
Submitter: Ambry Genetics
Inheritance Pattern: XL
Disease ID:MONDO:0026730
Submitter: ClinGen
*MSL3*, located on chromosome Xp22.2, encodes chromatin-associated male specific lethal (MSL) complex subunit 3, which is responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. MSL3 protein plays a critical role in a dosage-compensation pathway, equalizing X-linked gene expression in males and females. *MSL3* variants have been detected in unrelated patients with global developmental delay (PMID: 28135719), and further specifically identified to cause Basilicata-Akhtar syndrome (PMIDs: 30224647, 33173220). Clinical features of the syndrome include progressive gait disturbance, recognizable facial dysmorphism, hypotonia, feeding difficulties in early infancy, global delay in the acquisition of major milestones including walking and speech, and intellectual disability. *MSL3* variants lead to a heterogeneous pattern in patient cells compared to homogeneous intensity in control cells. Cells lacking functional MSL3 displayed a severe decrease in H4K16ac. In general, MSL3 causes an acute downregulation of numerous biologically relevant genes, including key developmental regulators. Some of the transcriptional and cellular phenotypes in patient cells are rescued by histone decetylase inhibitors (PMID: 30224647). Based on the consistent phenotypes in a high number of unrelated patients harboring *MSL3* variants reported across studies (PMIDs: 30224647, 33173220), and clear experimental evidence of the role of MSL3 in developmental processes, *MSL3* is definitively associated with Basilicata-Akhtar syndrome. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on January 18, 2022 (SOP Version 8).
Clinical Genomic Database (CGD)
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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to MSL3 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_078629.4. 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 | 12 | 9 | 1 | 22 | ||
| missense | 1 | 1 | 126 | 14 | 142 | |
| nonsense | 6 | 5 | 6 | 17 | ||
| start loss | 0 | |||||
| frameshift | 8 | 9 | 17 | |||
| splice donor/acceptor (+/-2bp) | 5 | 6 | 21 | 32 | ||
| Total | 20 | 21 | 165 | 23 | 1 | 230 |
Highest pathogenic variant AF is 9.5177813e-7
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_523353.2 | 13 | MANE Select | |
| Ensembl | ENSP00000312244.4 | 13 | MANE Select | |
| RefSeq | NP_001180199.1 | 13 | Standard | |
| RefSeq | NP_001269103.1 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Chromatin modifying enzymes
- HATs acetylate histones
- Chromatin organization
Biological Process
- chromatin silencing
- histone acetylation
- histone deacetylation
- histone H4 acetylation
- histone H2A acetylation
Molecular Function
- DNA binding
- methylated histone binding
Cellular Component
- histone acetyltransferase complex
- nucleoplasm
- NuA4 histone acetyltransferase complex
- MSL complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000312196
- Coding exons
- 13
- Length
- 17593
- 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 | 1.93 | 121 | 197 | 0.613 | 0.0000157 | 3439 |
| Missense (PolyPhen) | 24 | 69.397 | 0.34584 | 1335 | ||
| Synonymous | 0.672 | 63 | 70.2 | 0.898 | 0.00000554 | 942 |
| Loss of Function | 3.80 | 0 | 16.8 | 0.00 | 0.00000113 | 351 |
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:
- Function
- FUNCTION: May be involved in chromatin remodeling and transcriptional regulation. May have a role in X inactivation. Component of the MSL complex which is responsible for the majority of histone H4 acetylation at 'Lys-16' which is implicated in the formation of higher-order chromatin structure. Specifically recognizes histone H4 monomethylated at 'Lys-20' (H4K20Me1) in a DNA-dependent manner and is proposed to be involved in chromosomal targeting of the MSL complex. {ECO:0000269|PubMed:16227571, ECO:0000269|PubMed:20018852, ECO:0000269|PubMed:20657587, ECO:0000269|PubMed:20943666, ECO:0000269|PubMed:21217699, ECO:0000269|PubMed:22547026}.;
Recessive Scores
- pRec
- 0.0976
Intolerance Scores
- RVIS EVS
- -0.23
- RVIS percentile EVS
- 37.32
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.872
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |