H3-3A

Chr 1AD

H3.3 histone A

Also known as: BRYLIB1, H3.3A, H3F3, H3F3A

NCBI Gene: 3020 ENSG00000163041 UniProt: P84243 OMIM: 601128

This protein is a variant histone H3 that replaces conventional H3 in nucleosomes of active genes and serves as an epigenetic marker of transcriptionally active chromatin, being incorporated independently of DNA synthesis in non-dividing cells. Mutations cause Bryant-Li-Bhoj neurodevelopmental syndrome, an autosomal dominant condition affecting neurological development. The gene has a GeneReviews entry providing additional clinical guidance for evaluation and management.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

Histones are basic nuclear proteins that are responsible for the nucleosome structure of the chromosomal fiber in eukaryotes. Two molecules of each of the four core histones (H2A, H2B, H3, and H4) form an octamer, around which approximately 146 bp of DNA is wrapped in repeating units, called nucleosomes. The linker histone, H1, interacts with linker DNA between nucleosomes and functions in the compaction of chromatin into higher order structures. This gene contains introns and its mRNA is polyadenylated, unlike most histone genes. The protein encoded is a replication-independent member of the histone H3 family. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Bryant-Li-Bhoj neurodevelopmental syndrome 1MIM #619720

UniProtGlioma

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Bryant-Li-Bhoj neurodevelopmental syndrome 1 · AD · ClinGen 2024

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.16

LOEUF

—

Mechanism

📖

GeneReview available — H3-3A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

1.16LOEUF

pLI 0.123

Z-score 1.36

OE 0.37 (0.15–1.16)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

3.16Z-score

OE missense 0.06 (0.03–0.12)

5 obs / 88.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.37 (0.15–1.16)

0≤0.351.4

Missense OE?0.06 (0.03–0.12)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 2 / 5.4Missense obs/exp: 5 / 88.6Syn Z: -0.33

Background carrier burden — how many people carry a rare variant somewhere in H3-3A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 1,600

51 rare PASS variants

Rare truncating (LoF)

1 in 11,000

10 rare PASS variants

Rare synonymous (reference)

1 in 590

61 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for H3-3A. 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)	~556k	1 in 2,200	1 in 15,000
South Asian	~43k	1 in 2,500	1 in 1,600
Remaining (unassigned)	~30k	1 in 2,400	1 in 970
European (Finnish)	~27k	1 in 3,400	none seen
Admixed American	~22k	1 in 3,100	none seen
African / African American	~21k	1 in 3,900	≈ 1 in 13,000
East Asian	~20k	1 in 1,800	none seen
Ashkenazi Jewish	~13k	≈ 1 in 13,000	none seen
Middle Eastern	~2,884	none seen	≈ 1 in 2,900

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): 2 of 3 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: 2 of 3 (exon 4 below).? see exons ↓