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…

Primary Disease Associations & Inheritance

Basilicata-Akhtar syndromeMIM #301032

XLD

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Basilicata-Akhtar syndrome · XL · ClinGen 2022

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.18

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — X-linked: males carry a single copy

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

Background carrier burden — how many people carry a rare variant somewhere in MSL3?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

456 rare PASS variants

Rare truncating (LoF)

1 in 4,200

38 rare PASS variants

Rare synonymous (reference)

1 in 270

206 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MSL3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 230	1 in 10,000
South Asian	~36k	1 in 130	1 in 2,300
Remaining (unassigned)	~31k	1 in 140	1 in 2,600
European (Finnish)	~27k	1 in 1,000	≈ 1 in 6,600
Admixed American	~23k	1 in 130	≈ 1 in 5,300
African / African American	~21k	1 in 140	≈ 1 in 5,100
East Asian	~20k	1 in 150	1 in 1,500
Ashkenazi Jewish	~13k	1 in 360	none seen
Middle Eastern	~2,758	1 in 140	≈ 1 in 2,700

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 13 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 13.? see exons ↓