BCL11B

Chr 14AD

BCL11 transcription factor B

Also known as: ATL1, ATL1-alpha, ATL1-beta, ATL1-delta, ATL1-gamma, CTIP-2, CTIP2, IDDFSTA

NCBI Gene: 64919 ENSG00000127152 UniProt: Q9C0K0 OMIM: 606558

The protein encoded by this gene is a transcriptional repressor containing C2H2-type zinc fingers that regulates gene expression through chromatin remodeling complexes. Mutations cause autosomal dominant intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities, as well as severe combined immunodeficiency (SCID). The pathogenic mechanism involves loss of function, leading to disrupted transcriptional regulation critical for both neurodevelopment and T-cell function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a C2H2-type zinc finger protein and is closely related to BCL11A, a gene whose translocation may be associated with B-cell malignancies. Although the specific function of this gene has not been determined, the encoded protein is known to be a transcriptional repressor, and is regulated by the NURD nucleosome remodeling and histone deacetylase complex. Four alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Aug 2013]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.282 OMIM phenotypes

Clinical Summary— BCL11B

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Gene-Disease Validity (ClinGen)

intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalities · ADDefinitive

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 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

68 unique Pathogenic / Likely Pathogenic· 419 VUS of 948 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.28LOEUF

pLI 0.989

Z-score 3.99

OE 0.09 (0.04–0.28)

Highly constrained

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

Missense Constraint?

4.71Z-score

OE missense 0.43 (0.39–0.48)

237 obs / 547.2 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.28)

0≤0.351.4

Missense OE?0.43 (0.39–0.48)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 2 / 22.4Missense obs/exp: 237 / 547.2Syn Z: -1.35

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongBCL11B-related neurodevelopmental disorderLOFAD

This gene — mechanism propensity

0.3594th %ile

GOF

0.2597th %ile

LOF

0.86top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 84% of P/LP variants are LoF · LOEUF 0.28

DN1 literature citation

GOF1 literature citation

Literature Evidence

DNThe phenotype of the first de novo monoallelic germ line missense mutation in the BCL11B gene (encoding N441K) strongly implies that the mutant protein acts in a dominant-negative manner by neutralizing the unaffected protein through the formation of a nonfunctional dimer.1

GOFGiven that the prediction algorithm Zinc Finger Recognition Code (Najafabadi et al., 2015) suggests that both missense mutations are predicted to bind to different alternative genomic sequences (Supplementary Fig. 1B), we hypothesize that the here-identified missense mutation may have comparable e2

LOFTwo additional unrelated patients with a similar disorder carried de novo balanced translocations that interrupted a regulatory domain of the BCL11B gene. These patient cells showed about a 50% decrease in BCL11B mRNA, consistent with haploinsufficiency. The overall findings implicated BCL11B haploi2

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

References

ClinVar Variant Classifications

948 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35

Likely Pathogenic33

VUS419

Likely Benign381

Benign36

Conflicting33

Pathogenic

Likely Pathogenic

419

VUS

381

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	33	2	0	0	35
Likely Pathogenic	24	9	0	0	33
VUS	10	398	8	3	419
Likely Benign	0	28	27	326	381
Benign	0	25	5	6	36
Conflicting	—				33
Total	67	462	40	335	937

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 27) ClinVar copy-number / structural variants overlap BCL11B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →