MSL3

Summary

MSL3 (MSL complex subunit 3, HGNC:7370) is a protein-coding gene on chromosome Xp22.2, encoding MSL complex subunit 3 (Q8N5Y2). Non-catalytic component of the MSL histone acetyltransferase complex, a multiprotein complex that mediates the majority of histone H4 acetylation at ‘Lys-16’ (H4K16ac), an epigenetic mark that prevents chromatin compaction. It is haploinsufficient (ClinGen: sufficient evidence).

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.

Source: NCBI Gene 10943 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Basilicata-Akhtar syndrome (Definitive, ClinGen)
• Clinical variants (ClinVar): 241 total — 21 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 43
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_078629

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7370
Approved symbol	MSL3
Name	MSL complex subunit 3
Location	Xp22.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000005302
Ensembl biotype	protein_coding
OMIM	300609
Entrez	10943

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 30 protein_coding, 12 retained_intron, 8 nonsense_mediated_decay

ENST00000312196, ENST00000337339, ENST00000361672, ENST00000380691, ENST00000380692, ENST00000380693, ENST00000398527, ENST00000421368, ENST00000467141, ENST00000468149, ENST00000473380, ENST00000476743, ENST00000478462, ENST00000482871, ENST00000483645, ENST00000494268, ENST00000647599, ENST00000647701, ENST00000647839, ENST00000647857, ENST00000647869, ENST00000647985, ENST00000648013, ENST00000648120, ENST00000648207, ENST00000648287, ENST00000648545, ENST00000648614, ENST00000648656, ENST00000648692, ENST00000648889, ENST00000648918, ENST00000649078, ENST00000649130, ENST00000649271, ENST00000649308, ENST00000649420, ENST00000649602, ENST00000649649, ENST00000649684, ENST00000649685, ENST00000649785, ENST00000649797, ENST00000649851, ENST00000649988, ENST00000650050, ENST00000650106, ENST00000650215, ENST00000650370, ENST00000650628

RefSeq mRNA: 5 — MANE Select: NM_078629 NM_001193270, NM_001282174, NM_006800, NM_078628, NM_078629

CCDS: CCDS14147, CCDS14148, CCDS14149, CCDS55369, CCDS65213

Canonical transcript exons

ENST00000312196 — 13 exons

Exon	Start	End
ENSE00002281076	11758237	11758365
ENSE00003459000	11761500	11761582
ENSE00003467194	11768573	11768682
ENSE00003502417	11759793	11759875
ENSE00003507101	11763780	11763938
ENSE00003531274	11772156	11772255
ENSE00003532251	11762130	11762252
ENSE00003539822	11762837	11762997
ENSE00003554346	11765467	11765729
ENSE00003606679	11760403	11760498
ENSE00003614362	11760837	11760937
ENSE00003669782	11772621	11772705
ENSE00003837008	11774980	11775772

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 95.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.7585 / max 280.3015, expressed in 1766 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195496	6.9297	1728
195503	3.4162	446
195499	2.1628	937
195497	0.4433	193
195494	0.2103	70
195501	0.1831	75
195495	0.1235	45
209601	0.1073	46
195502	0.1003	52
195498	0.0678	30

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	95.88	gold quality
mononuclear cell	CL:0000842	95.82	gold quality
leukocyte	CL:0000738	95.72	gold quality
granulocyte	CL:0000094	94.97	gold quality
lymph node	UBERON:0000029	94.24	gold quality
spleen	UBERON:0002106	93.87	gold quality
blood	UBERON:0000178	93.80	gold quality
secondary oocyte	CL:0000655	93.64	gold quality
buccal mucosa cell	CL:0002336	93.50	gold quality
oocyte	CL:0000023	93.35	gold quality
vermiform appendix	UBERON:0001154	92.31	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	92.30	gold quality
cortical plate	UBERON:0005343	92.26	gold quality
calcaneal tendon	UBERON:0003701	92.25	gold quality
sural nerve	UBERON:0015488	92.25	gold quality
bone marrow cell	CL:0002092	90.89	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.58	gold quality
tonsil	UBERON:0002372	90.53	gold quality
caecum	UBERON:0001153	90.31	gold quality
right lung	UBERON:0002167	90.23	gold quality
muscle of leg	UBERON:0001383	90.20	gold quality
gastrocnemius	UBERON:0001388	90.16	gold quality
bone marrow	UBERON:0002371	90.10	gold quality
stromal cell of endometrium	CL:0002255	89.05	gold quality
epithelium of nasopharynx	UBERON:0001951	88.70	gold quality
nasopharynx	UBERON:0001728	88.69	gold quality
ganglionic eminence	UBERON:0004023	88.63	gold quality
lower esophagus mucosa	UBERON:0035834	88.45	gold quality
prefrontal cortex	UBERON:0000451	88.43	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.35	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.99

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

60 targeting MSL3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-372-5P	99.41	69.11	2299

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 4)

• A multisubunit human histone acetylase complex that contains homologs of the Drosophila MSL proteins MOF, MSL1 (hampin A), MSL2, and MSL3 was described. This complex is responsible for histone H4 lysine-16 acetylation of all cellular chromosomes. (PMID:16227571)
• MSL3 plays an important role in targeting the male specific lethal complex to chromatin in both humans and flies by binding to H4K20Me(1). (PMID:20943666)
• Characterization of syndrome that allowed us to decipher the developmental importance of MSL3 in humans. (PMID:30224647)
• Defining the genotypic and phenotypic spectrum of X-linked MSL3-related disorder. (PMID:33173220)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
mus_musculus	Msl3	ENSMUSG00000031358
rattus_norvegicus	Msl3	ENSRNOG00000004016
drosophila_melanogaster	msl-3	FBGN0002775
caenorhabditis_elegans		WBGENE00003406
caenorhabditis_elegans		WBGENE00012551

Paralogs (3): MORF4L2 (ENSG00000123562), MORF4L1 (ENSG00000185787), MSL3B (ENSG00000293137)

Protein

Protein identifiers

MSL complex subunit 3 — Q8N5Y2 (reviewed: Q8N5Y2)

Alternative names: Male-specific lethal 3 homolog, Male-specific lethal-3 homolog 1, Male-specific lethal-3 protein-like 1

All UniProt accessions (25): Q8N5Y2, A0A3B3IRI6, A0A3B3IRN2, A0A3B3IRT2, A0A3B3IS16, A0A3B3IS72, A0A3B3ISB4, A0A3B3IT49, A0A3B3IT59, A0A3B3ITF3, A0A3B3ITF8, A0A3B3ITH5, A0A3B3ITL5, A0A3B3ITV8, A0A3B3ITX5, A0A3B3IU53, A0A3B3IU64, A0A3B3IU80, A0A3B3IUB0, A0A3F2YNX2, A6NLU8, C9JKR8, C9JXM9, F8WC61, H7BYE4

UniProt curated annotations — full annotation on UniProt →

Function. Non-catalytic component of the MSL histone acetyltransferase complex, a multiprotein complex that mediates the majority of histone H4 acetylation at ‘Lys-16’ (H4K16ac), an epigenetic mark that prevents chromatin compaction. The MSL complex is required for chromosome stability and genome integrity by maintaining homeostatic levels of H4K16ac. The MSL complex is also involved in gene dosage by promoting up-regulation of genes expressed by the X chromosome. X up-regulation is required to compensate for autosomal biallelic expression. The MSL complex also participates in gene dosage compensation by promoting expression of Tsix non-coding RNA. Acts as a histone reader that specifically recognizes and binds 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. May play a role X inactivation in females.

Subunit / interactions. Component of the MSL histone acetyltransferase complex at least composed of the KAT8/MOF, MSL1/hampin, MSL2 and MSL3. Interacts (via the MRG domain) with MSL1 and KAT8/MOF.

Subcellular location. Nucleus.

Tissue specificity. Expressed in many tissues including liver, pancreas, heart, lung, kidney, skeletal muscle, brain, and placenta, with highest expression in skeletal muscle and heart.

Disease relevance. Basilicata-Akhtar syndrome (MRXSBA) [MIM:301032] An X-linked syndrome characterized by intellectual disability, global developmental delay, progressive gait disturbance, poor or absent speech, facial dysmorphism, and mild distal skeletal anomalies. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. MSL3L1 gene undergoes X inactivation.

Isoforms (6)

UniProt ID	Names	Canonical?
Q8N5Y2-1	1	yes
Q8N5Y2-2	2
Q8N5Y2-3	3
Q8N5Y2-4	4
Q8N5Y2-5	5
Q8N5Y2-6	6

RefSeq proteins (5): NP_001180199, NP_001269103, NP_006791, NP_523352, NP_523353* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000953	Chromo/chromo_shadow_dom	Domain
IPR008676	MRG	Family
IPR016197	Chromo-like_dom_sf	Homologous_superfamily
IPR026541	MRG_dom	Domain
IPR038217	MRG_C_sf	Homologous_superfamily
IPR053820	MSL3_chromo-like	Domain

Pfam: PF05712, PF22732

UniProt features (68 total): sequence variant 18, helix 13, splice variant 8, modified residue 7, mutagenesis site 5, strand 5, region of interest 3, sequence conflict 3, compositionally biased region 3, domain 2, chain 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3OA6	X-RAY DIFFRACTION	2.35
3OB9	X-RAY DIFFRACTION	2.5
2Y0N	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N5Y2-F1	69.25	0.39

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (7): 311, 367, 400, 405, 407, 411, 309

Mutagenesis-validated functional residues (5):

Position	Phenotype
31	diminishes interaction with histone h4 monomethylated at ’lys-20’(h4k20me1).
55	diminishes dna-binding; when associated with a-65.
56	abolishes interaction with histone h4 monomethylated at ’lys-20’(h4k20me1).
59	diminishes dna-binding.
65	diminishes dna-binding; when associated with a-55.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-3214847	HATs acetylate histones
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-4839726	Chromatin organization

MSigDB gene sets: 314 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, RRAGTTGT_UNKNOWN, MORF_MSH3, MORF_BRCA1, MORF_ATRX, MORF_ESR1, MORF_RAD51L3, FOXD3_01, FOXJ2_01, HFH4_01, BENPORATH_ES_CORE_NINE_CORRELATED, MORF_RAP1A, HFH1_01, MAF_Q6

GO Biological Process (4): regulation of DNA-templated transcription (GO:0006355), positive regulation of DNA-templated transcription (GO:0045893), chromatin organization (GO:0006325), regulation of gene expression (GO:0010468)

GO Molecular Function (4): DNA binding (GO:0003677), histone H4K16ac reader activity (GO:0140046), histone reader activity (GO:0140566), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), NuA4 histone acetyltransferase complex (GO:0035267), MSL complex (GO:0072487)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Chromatin modifying enzymes	1
Chromatin organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA-templated transcription	2
regulation of gene expression	1
regulation of RNA biosynthetic process	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
cellular component organization	1
gene expression	1
regulation of macromolecule biosynthetic process	1
nucleic acid binding	1
histone H4 reader activity	1
nucleosome	1
histone binding	1
chromatin-protein adaptor activity	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
H4/H2A histone acetyltransferase complex	1
H4 histone acetyltransferase complex	1

Protein interactions and networks

STRING

1674 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MSL3	MSL2	Q9HCI7	999
MSL3	MSL1	Q68DK7	980
MSL3	KAT8	Q9H7Z6	839
MSL3	H4C7	Q99525	759
MSL3	H4C16	P02304	755
MSL3	KANSL2	Q9H9L4	563
MSL3	CBX8	Q9HC52	543
MSL3	NUP153	P49790	506
MSL3	MCRS1	Q96EZ8	506
MSL3	TBL1X	O60907	470
MSL3	ARHGAP6	O43182	469
MSL3	SETD2	Q9BYW2	465
MSL3	KANSL1	Q7Z3B3	461
MSL3	DHX9	Q08211	460
MSL3	MORF4L2	Q15014	458

IntAct

41 interactions, top by confidence:

A	B	Type	Score
MSL3	MSL1	psi-mi:“MI:0914”(association)	0.760
KAT8	MSL1	psi-mi:“MI:0914”(association)	0.640
MSL3	WFS1	psi-mi:“MI:0915”(physical association)	0.560
PBK	TRIM37	psi-mi:“MI:0914”(association)	0.550
MSL1	MSL3B	psi-mi:“MI:0914”(association)	0.530
PLEKHA1	PBX2	psi-mi:“MI:0914”(association)	0.530
POLR2I	SUPT5H	psi-mi:“MI:0914”(association)	0.530
MSL2	HBB	psi-mi:“MI:0914”(association)	0.530
BOD1	PLXDC2	psi-mi:“MI:0914”(association)	0.530
DYRK1B	BMAL1	psi-mi:“MI:0914”(association)	0.530
MSL3	CDK6	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
H3C1	SMCHD1	psi-mi:“MI:2364”(proximity)	0.410
Kat8	PHF20L1	psi-mi:“MI:0915”(physical association)	0.400
Kat8	HCFC1	psi-mi:“MI:0914”(association)	0.350
MSL2	IGHG2	psi-mi:“MI:0914”(association)	0.350
BOD1	BPGM	psi-mi:“MI:0914”(association)	0.350
CEP43	POTEI	psi-mi:“MI:0914”(association)	0.350
MSL3	TUBA1B	psi-mi:“MI:0914”(association)	0.350
KAT8	HCFC1	psi-mi:“MI:0914”(association)	0.350
KAT8	MSL3B	psi-mi:“MI:0914”(association)	0.350

BioGRID (54): PAF1 (Reconstituted Complex), MSL3 (Affinity Capture-MS), MSL3 (Affinity Capture-MS), MSL3 (Affinity Capture-MS), MSL3 (Proximity Label-MS), MSL3 (Proximity Label-MS), MSL3 (Affinity Capture-MS), MSL3 (Affinity Capture-MS), MSL3 (Affinity Capture-MS), MSL3 (Affinity Capture-MS), MSL3 (Affinity Capture-MS), MSL3 (Affinity Capture-MS), MSL3 (Affinity Capture-MS), MSL3 (Affinity Capture-MS), MSL3 (Affinity Capture-RNA)

ESM2 similar proteins: A0JPP1, A0JPQ7, A2VDN6, E6ZGB4, O75151, O75376, O88974, P0CH95, P22682, P55265, P55266, Q14919, Q15047, Q15459, Q17R89, Q2YDP3, Q3UIA2, Q3YEC7, Q4KKX4, Q4V7W5, Q5F3B1, Q5R6Y9, Q5SFM8, Q5U3K5, Q60974, Q61909, Q68EM7, Q6P949, Q6ZM86, Q80TJ7, Q86XZ4, Q8CFK2, Q8K1N4, Q8K4S7, Q8K4Z5, Q8N5Y2, Q8R3Y5, Q8VHI6, Q8VI24, Q92625

Diamond homologs: A5A6J5, A7DTF0, G3X992, O13953, P0C860, P0CO86, P0CO87, P60762, Q12432, Q15014, Q4P827, Q4R578, Q4V3E2, Q4WPW2, Q54RM0, Q59K07, Q5BBV4, Q5NVP9, Q5R6Y9, Q5R905, Q6AYG1, Q6AYU1, Q6BT38, Q6C9M9, Q6CND0, Q6QI89, Q75AH9, Q8N5Y2, Q94C32, Q9R0Q4, Q9UBU8, Q9WVG9, Q9Y0I1, P50536, Q9NBL2, A2CG63, F8VPQ2, P29374, Q4LE39

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MSL3	“form complex”	“MSL acetyltransferase”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
HATs acetylate histones	7	22.2×	6e-06
Oxidative Stress Induced Senescence	5	18.1×	7e-04
Estrogen-dependent gene expression	5	15.1×	1e-03
Dengue Virus-Host Interactions	5	9.1×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

241 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	16
Uncertain significance	78
Likely benign	24
Benign	3

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1065483	NM_078629.4(MSL3):c.607C>T (p.Gln203Ter)	Pathogenic
1210216	NM_078629.4(MSL3):c.1171+2T>A	Pathogenic
1320251	NM_078629.4(MSL3):c.1226_1229del (p.Glu409fs)	Pathogenic
1700027	NM_078629.4(MSL3):c.590_593del	Pathogenic
1707503	NM_078629.4(MSL3):c.973_974del (p.Gln326fs)	Pathogenic
1708509	NM_078629.4(MSL3):c.1282-249_1382-154del	Pathogenic
2430277	NM_078629.4(MSL3):c.547C>T (p.Gln183Ter)	Pathogenic
2499568	NM_078629.4(MSL3):c.1105C>T (p.Gln369Ter)	Pathogenic
2579184	GRCh38/hg38 Xp22.2(chrX:11766227-11770962)x0	Pathogenic
3340966	NM_078629.4(MSL3):c.1373G>A (p.Arg458Gln)	Pathogenic
3398995	NM_078629.4(MSL3):c.909-1G>A	Pathogenic
4755485	NM_078629.4(MSL3):c.749+5G>A	Pathogenic
520841	NM_078629.4(MSL3):c.1208del (p.Pro403fs)	Pathogenic
817066	NM_078629.4(MSL3):c.1319dup (p.Gly441fs)	Pathogenic
817495	NM_078629.4(MSL3):c.1168_1169del (p.Lys390fs)	Pathogenic
827787	NM_078629.4(MSL3):c.971_974del (p.Glu324fs)	Pathogenic
976667	NM_078629.4(MSL3):c.1314C>A (p.Tyr438Ter)	Pathogenic
984579	NM_078629.4(MSL3):c.1171+1G>A	Pathogenic
985202	NM_078629.4(MSL3):c.1360C>T (p.Gln454Ter)	Pathogenic
985435	NM_078629.4(MSL3):c.709_715dup (p.Asn239fs)	Pathogenic
985508	NM_078629.4(MSL3):c.1125_1141dup (p.Met381fs)	Pathogenic
1285436	NM_078629.4(MSL3):c.872_876del (p.Phe291fs)	Likely pathogenic
3255017	NM_078629.4(MSL3):c.750-2A>G	Likely pathogenic
3382675	NM_078629.4(MSL3):c.1220dup (p.Ser407fs)	Likely pathogenic
4056626	NM_078629.4(MSL3):c.1347C>A (p.Tyr449Ter)	Likely pathogenic
4057283	NM_078629.4(MSL3):c.1211dup (p.Thr405fs)	Likely pathogenic
4111269	NM_078629.4(MSL3):c.1281+1G>A	Likely pathogenic
4538514	NM_078629.4(MSL3):c.588+1del	Likely pathogenic
4814223	NM_078629.4(MSL3):c.980dup (p.Thr328fs)	Likely pathogenic
487564	NM_078629.4(MSL3):c.1381+1G>T	Likely pathogenic

SpliceAI

1745 predictions. Top by Δscore:

Variant	Effect	Δscore
X:11758348:GTGCT:G	donor_gain	1.0000
X:11758364:AG:A	donor_loss	1.0000
X:11758365:GGTG:G	donor_loss	1.0000
X:11758366:G:GG	donor_loss	1.0000
X:11758381:G:T	donor_gain	1.0000
X:11758386:G:GT	donor_gain	1.0000
X:11758387:G:T	donor_gain	1.0000
X:11758390:G:GT	donor_gain	1.0000
X:11759785:C:CA	acceptor_gain	1.0000
X:11759789:TCA:T	acceptor_loss	1.0000
X:11759790:CAG:C	acceptor_loss	1.0000
X:11759791:A:AG	acceptor_gain	1.0000
X:11759791:A:T	acceptor_loss	1.0000
X:11759792:G:GG	acceptor_gain	1.0000
X:11759792:GATT:G	acceptor_gain	1.0000
X:11759872:GAAG:G	donor_gain	1.0000
X:11759875:GGT:G	donor_loss	1.0000
X:11759876:G:GA	donor_loss	1.0000
X:11759876:G:GG	donor_gain	1.0000
X:11759877:T:G	donor_loss	1.0000
X:11760397:A:AG	acceptor_gain	1.0000
X:11760401:A:AG	acceptor_gain	1.0000
X:11760401:AGCT:A	acceptor_gain	1.0000
X:11760401:AGCTG:A	acceptor_gain	1.0000
X:11760402:G:GA	acceptor_gain	1.0000
X:11760402:GCT:G	acceptor_gain	1.0000
X:11760402:GCTG:G	acceptor_gain	1.0000
X:11760402:GCTGG:G	acceptor_gain	1.0000
X:11760466:GC:G	donor_gain	1.0000
X:11760495:GCCT:G	donor_gain	1.0000

AlphaMissense

3458 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:11758294:T:C	F11L	1.000
X:11758296:C:A	F11L	1.000
X:11758296:C:G	F11L	1.000
X:11758316:T:A	L18Q	1.000
X:11758316:T:C	L18P	1.000
X:11758318:T:C	C19R	1.000
X:11758319:G:A	C19Y	1.000
X:11758320:C:G	C19W	1.000
X:11758321:T:C	F20L	1.000
X:11758322:T:C	F20S	1.000
X:11758322:T:G	F20C	1.000
X:11758323:C:A	F20L	1.000
X:11758323:C:G	F20L	1.000
X:11758326:G:C	E21D	1.000
X:11758326:G:T	E21D	1.000
X:11758327:C:T	P22S	1.000
X:11758341:G:C	K26N	1.000
X:11758341:G:T	K26N	1.000
X:11758352:T:A	L30Q	1.000
X:11758352:T:C	L30P	1.000
X:11758354:T:C	Y31H	1.000
X:11758360:G:C	A33P	1.000
X:11758361:C:A	A33D	1.000
X:11758361:C:T	A33V	1.000
X:11759844:T:C	Y52H	1.000
X:11759844:T:G	Y52D	1.000
X:11759845:A:C	Y52S	1.000
X:11759848:T:C	L53P	1.000
X:11759851:T:A	I54N	1.000
X:11759851:T:G	I54S	1.000

dbSNP variants (sampled 300 via entrez): RS1000173511 (X:11769954 C>A,T), RS1000204598 (X:11769707 G>A), RS1000213999 (X:11775949 T>A), RS1000406803 (X:11761462 T>C), RS1000673661 (X:11761129 G>A), RS1000875510 (X:11761067 G>C), RS1000918924 (X:11769778 C>T), RS1001215330 (X:11771205 A>G), RS1001276923 (X:11761237 A>G), RS1001286704 (X:11763492 C>T), RS1001307015 (X:11771491 C>G), RS1001462285 (X:11772011 A>C), RS1001708569 (X:11761911 G>A,T), RS1001858485 (X:11756258 C>A), RS1002328169 (X:11765696 A>G)

Disease associations

OMIM: gene MIM:300609 | disease phenotypes: MIM:301032

GenCC curated gene-disease

Disease	Classification	Inheritance
Basilicata-Akhtar syndrome	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Basilicata-Akhtar syndrome	Definitive	XL

Mondo (2): Basilicata-Akhtar syndrome (MONDO:0026730), intellectual disability (MONDO:0001071)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

43 total (30 of 43 shown, HPO-id order):

HPO	Term
HP:0000268	Dolichocephaly
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000319	Smooth philtrum
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000384	Preauricular skin tag
HP:0000452	Choanal stenosis
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000490	Deeply set eye
HP:0000494	Downslanted palpebral fissures
HP:0000506	Telecanthus
HP:0000708	Atypical behavior
HP:0000750	Delayed speech and language development
HP:0000826	Precocious puberty
HP:0000954	Single transverse palmar crease
HP:0001028	Hemangioma
HP:0001181	Adducted thumb
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001290	Generalized hypotonia
HP:0001344	Absent speech
HP:0001423	X-linked dominant inheritance
HP:0001769	Broad foot
HP:0001773	Short foot
HP:0001998	Neonatal hypoglycemia
HP:0002020	Gastroesophageal reflux

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

30 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	8
trichostatin A	affects cotreatment, decreases expression	2
entinostat	decreases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
beta-lapachone	decreases expression, increases expression	1
methacrylaldehyde	decreases expression, increases abundance, affects cotreatment	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Acrolein	decreases expression, increases abundance, affects cotreatment	1
Air Pollutants	increases abundance, affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Caffeine	increases phosphorylation	1
Doxorubicin	decreases expression	1
Gallic Acid	decreases expression	1
Hydrogen Peroxide	affects expression	1
Lead	increases expression	1
Ozone	affects cotreatment, decreases expression, increases abundance	1
Tretinoin	increases expression	1
Gold Compounds	decreases expression	1
Asbestos, Crocidolite	decreases expression	1
Antirheumatic Agents	decreases expression	1
Palmitic Acid	increases phosphorylation	1
Volatile Organic Compounds	affects cotreatment, decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4F8	SEES3-1V human MSL3L1, clone1	Embryonic stem cell	Male
CVCL_A4F9	SEES3-1V human MSL3L1, clone2	Embryonic stem cell	Male
CVCL_A4G0	SEES3-1V human MSL3L1, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

197 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders