BCL9

protein-coding

BCL9 transcription coactivator, the group of Wnt enhanceosome complex

Gene summary

BCL9 is associated with B-cell acute lymphoblastic leukemia. It may be a target of translocation in B-cell malignancies with abnormalities of 1q21. Its function is unknown. The overexpression of BCL9 may be of pathogenic significance in B-cell malignancies. [provided by RefSeq, Jul 2008]

MANE transcript

NM_004326.4

Inheritance

ClinVar variants

U:236B:16

Top phenotype

BCL9-related disorder

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr1:147,541,501-147,626,216

External References & Databases

Ensembl (ENSG00000116128)

Transcript & Mutation Effects

hg38 • Region Span ~84.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*BCL9* was first reported in relation to autosomal dominant congenital heart disease in 2020 (Edwards et al., PMID: 32368696). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: Congenital heart defect (CHD) and left ventricular outflow tract obstruction. Two variants (a missense and a nonsense variant) that have been reported in two probands in two publications (PMIDs: 32368696, 33084842) are included in this curation. Although *BCL9* is nearly constrained for loss of function based on its z-score, more evidence is needed to confirm the mechanism of disease for this gene. No experimental evidence supporting the role of BCL9 in autosomal dominant CHD was found. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 9/11/23 (SOP Version 9).

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to BCL9 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 232

not providedTotal: 12

BCL9-related disorderTotal: 5

Congenital long QT syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004326.4. 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			1 clinvar	6 clinvar	1 clinvar	8
missense			231 clinvar	7 clinvar	2 clinvar	240
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	236	13	3	252

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004326.4	RefSeq	NP_004317.2	7	MANE Select
ENST00000234739.8	Ensembl	ENSP00000234739.3	7	MANE Select
ENST00000683836.1	Ensembl	ENSP00000506908.1	7	Standard
ENST00000683836.2	Ensembl	ENSP00000506908.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

WNT-Ncore
Wnt Signaling Pathway
Wnt-beta-catenin Signaling Pathway in Leukemia
Signaling by WNT
Signal Transduction

Biological Process

myotube differentiation involved in skeletal muscle regeneration
regulation of transforming growth factor beta receptor signaling pathway
somatic stem cell population maintenance
skeletal muscle cell differentiation
positive regulation of transcription by RNA polymerase II

Molecular Function

transcription coactivator activity
protein binding
beta-catenin binding

Cellular Component

nucleoplasm
cis-Golgi network
beta-catenin-TCF complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000234739
Coding exons: 7
Length: 84836
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125748
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0352	837	840	0.997	0.0000460	9341
Missense (PolyPhen)		352	363.8	0.96756		3953
Synonymous	-2.10	353	306	1.15	0.0000173	3049
Loss of Function	4.65	9	41.2	0.218	0.00000249	413

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00025	rare
Latino/Admixed American	0.00012	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000055	0.000054	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00022	0.00019	rare
South Asian	0.000066	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in signal transduction through the Wnt pathway. Promotes beta-catenin's transcriptional activity (By similarity). {ECO:0000250, ECO:0000269|PubMed:11955446}.;

Recessive Scores

pRec: 0.119

Intolerance Scores

LoFtool: 0.250
RVIS EVS: -1.63
RVIS percentile EVS: 2.88

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.955

Gene Damage Prediction

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