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

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]

Primary Disease Associations & Inheritance

Immunodeficiency 49, severe combinedMIM #617237

Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalitiesMIM #618092

555

ClinVar variants

Pathogenic / LP

0.99

pLI score· haploinsufficient

Active trials

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

72 Pathogenic / Likely Pathogenic· 239 VUS of 555 total submissions

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Clinical Trials

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

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.09 (0.04–0.28)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.43 (0.39–0.48)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.10

0≤1.21.6

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