MSL3

Chr XXLD

MSL complex subunit 3

Also known as: MRSXBA, MRXS36, MRXSBA, MSL3L1

NCBI Gene: 10943 ENSG00000005302 UniProt: Q8N5Y2 OMIM: 300609

MSL3 encodes a non-catalytic component of the MSL histone acetyltransferase complex that mediates histone H4 acetylation at lysine-16, maintaining chromosome stability and regulating X-linked gene expression. Mutations cause Basilicata-Akhtar syndrome with X-linked dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI = 1.00, LOEUF = 0.18), indicating that mutations are likely to have significant functional consequences.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLDLOEUF 0.181 OMIM phenotype

Clinical Summary— MSL3

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Gene-Disease Validity (ClinGen)

Basilicata-Akhtar syndrome · XLDefinitive

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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ClinVar Variants

31 unique Pathogenic / Likely Pathogenic· 79 VUS of 236 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.18LOEUF

pLI 0.997

Z-score 3.80

OE 0.00 (0.00–0.18)

Highly constrained

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

Missense Constraint?

1.93Z-score

OE missense 0.61 (0.53–0.71)

121 obs / 197.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.18)

0≤0.351.4

Missense OE?0.61 (0.53–0.71)

0≤0.61.4

Synonymous OE?0.90

0≤1.21.6

LoF obs/exp: 0 / 16.8Missense obs/exp: 121 / 197.4Syn Z: 0.67

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMSL3-related intellectual developmental disorderLOFmonoallelic_X_heterozygous

This gene — mechanism propensity

0.2499th %ile

GOF

0.1899th %ile

LOF

0.81top 5%

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

LOFprediction above median · 94% of P/LP variants are LoF · LOEUF 0.18 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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

ClinVar Variant Classifications

236 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic20

Likely Pathogenic11

VUS79

Likely Benign25

Benign4

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	1	1	0	20
Likely Pathogenic	11	0	0	0	11
VUS	2	75	2	0	79
Likely Benign	0	13	6	6	25
Benign	0	0	2	2	4
Conflicting	—				1
Total	31	89	11	8	140

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

84 pathogenic / likely-pathogenic (of 99) ClinVar copy-number / structural variants overlap MSL3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →