BCL11B

protein-coding

BCL11 transcription factor B, the group of Zinc fingers C2H2-type|BAF complex

Gene summary

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]

Previous symbols:

ZNF856B

MANE transcript

NM_138576.4

Inheritance

ClinVar variants

P:78U:422B:421

Top phenotype

Immunodeficiency 49, severe combined; Intellectual developmental disorder with speech delay, dysmorphic facies, and T-cell abnormalities

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chr14:99,169,287-99,272,197

External References & Databases

Ensembl (ENSG00000127152)

Transcript & Mutation Effects

hg38 • Region Span ~102.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0060763

Submitter: ClinGen

BCL11B was first reported in relation to autosomal dominant BCL11B-related BAFopathy in 2016 (Punwani et al., PMID: 27959755). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, Immunodeficiency 49, severe combined (OMIM:617237) and Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities (OMIM:618092). Affected individuals have delayed psychomotor development, intellectual disability, speech delay, dysmorphic features, dental anomalies, recurrent infections, low or poor proliferation of T-cells, and allergic disease in some. 15 variants (missense, nonsense, and frameshift) that have been reported in 15 probands in four publications (PMIDs: 27959755, 29985992, 37860968, 33194885) are included in this curation. All of variants occurred likely de novo with confirmed parental relatedness and 12 of the 13 truncations occurred in the last exon. The mechanism of pathogenicity is known to be loss of DNA binding function either by dominant negative or haploinsufficiency. This gene-disease relationship is also supported by animal models, rescue studies, expression studies, and functional alteration studies (PMIDs: 27959755, 22588081, 20538915, 28951542). BCL11B is expressed in T-cells and is required for T-cell development. Knockout mice have reduced neuronal progenitor cell proliferation and impaired neuronal differentiation. Introduction of human BCL11B rescued the arrest in T-cell development and corrected the craniofacial abnormalities caused by bcl11ba knockdown in Zebrafish. BCL11B forms a homodimer and a heterodimer with BCL11A. BCL11B pathogenic variants interfere with the function of both BCL11A and BCL11B in suppressing NK cell-related gene expression. In summary, there is definitive evidence supporting the relationship between BCL11B and autosomal dominant BCL11B-related BAFopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.This classification was approved by the ClinGen SCID-CID GCEP on the meeting date December 19, 2024 (SOP Version 11).

intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalitiesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0060763

Submitter: Ambry Genetics

intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060763

Submitter: PanelApp Australia

immunodeficiency 49STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014981

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 49LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014981

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0060763

Submitter: Ambry Genetics

immunodeficiency 49LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014981

Submitter: Ambry Genetics

intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0060763

Submitter: Illumina

intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0060763

Submitter: G2P

Clinical Genomic Database (CGD)

Immunodeficiency 49, severe combined; Intellectual developmental disorder with speech delay, dysmorphic facies, and T-cell abnormalitiesAD

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Dental; Dermatologic; Neurologic; Musculoskeletal

Intervention: Allergy/Immunology/Infectious

Rationale: Among other features, individuals have been described as susceptible to severe or frequent infections, and awareness may allow preventative measures and early and aggressive treatment of infections; In Immunodeficiency 49, HSCT has been described

Refs: 27959755; 29985992

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BCL11B variants in ClinVar

12 Conditions Cataloged

not providedTotal: 825

Inborn genetic diseasesTotal: 115

not specifiedTotal: 103

Intellectual developmental disorder with speech delay, dysmorphic facies, and t-cell abnormalitiesTotal: 67

BCL11B-related disorderTotal: 45

Immunodeficiency 49Total: 22

See casesTotal: 3

Combined immunodeficiencyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_138576.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			4 clinvar	350 clinvar	2 clinvar	356
missense	2 clinvar	12 clinvar	407 clinvar	48 clinvar	21 clinvar	490
nonsense	6 clinvar	6 clinvar	1 clinvar			13
start loss		1 clinvar				1
frameshift	26 clinvar	24 clinvar	9 clinvar			59
splice donor/acceptor (+/-2bp)	1 clinvar		1 clinvar			2
Total	35	43	422	398	23	921

Highest pathogenic variant AF is 0.000002767691

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 11 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_138576.4	RefSeq	NP_612808.1	4	MANE Select
ENST00000357195.8	Ensembl	ENSP00000349723.3	4	MANE Select
NM_001282237.2	RefSeq	NP_001269166.1	4	Standard
NM_001282238.2	RefSeq	NP_001269167.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Transcriptional misregulation in cancer - Homo sapiens (human)
Development and heterogeneity of the ILC family

Biological Process

keratinocyte development
epithelial cell morphogenesis
regulation of transcription, DNA-templated
negative regulation of cell population proliferation
regulation of keratinocyte proliferation

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription factor activity
protein binding
sequence-specific DNA binding

Cellular Component

nucleus
neuron projection

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000357195
Coding exons: 4
Length: 102238
Individuals with no LoFs: 124392
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 124394
p: 0.00000804

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.71	237	547	0.433	0.0000408	5691
Missense (PolyPhen)		21	95.167	0.22066		966
Synonymous	-1.35	314	285	1.10	0.0000265	1827
Loss of Function	3.99	2	22.4	0.0895	0.00000110	259

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000030	0.000029	rare
Ashkenazi Jewish	0.00010	0.00010	rare
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Key regulator of both differentiation and survival of T- lymphocytes during thymocyte development in mammals. Essential in controlling the responsiveness of hematopoietic stem cells to chemotactic signals by modulating the expression of the receptors CCR7 and CCR9, which direct the movement of progenitor cells from the bone marrow to the thymus (PubMed:27959755). Is a regulator of IL2 promoter and enhances IL2 expression in activated CD4(+) T- lymphocytes (PubMed:16809611). Tumor-suppressor that represses transcription through direct, TFCOUP2-independent binding to a GC- rich response element (By similarity). May also function in the P53-signaling pathway (By similarity). {ECO:0000250|UniProtKB:Q99PV8, ECO:0000269|PubMed:16809611, ECO:0000269|PubMed:27959755}.;
Disease: DISEASE: Immunodeficiency 49 (IMD49) [MIM:617237]: A form of severe combined immunodeficiency characterized by severe T-cell lymphopenia, no detectable T-cell receptor excision circles, no naive helper CD4+ T-cells, and impaired T-cell proliferative response. In addition to primary immunodeficiency, affected individuals manifest multiple abnormal systemic features, including severe delayed psychomotor development, intellectual disability, spastic quadriplegia, and craniofacial abnormalities. {ECO:0000269|PubMed:27959755}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.162

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.973

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium