CD79A

protein-coding

CD79a molecule, the group of V-set domain containing|CD molecules

Gene summary

The B lymphocyte antigen receptor is a multimeric complex that includes the antigen-specific component, surface immunoglobulin (Ig). Surface Ig non-covalently associates with two other proteins, Ig-alpha and Ig-beta, which are necessary for expression and function of the B-cell antigen receptor. This gene encodes the Ig-alpha protein of the B-cell antigen component. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

Previous symbols:

MANE transcript

NM_001783.4

Inheritance

AR, AD

ClinVar variants

P:8U:77B:60

Top phenotype

Agammaglobulinemia 3, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.16

Max pathogenic AF

—

Genomic locus

chr19:41,877,279-41,881,372

External References & Databases

Ensembl (ENSG00000105369)

Transcript & Mutation Effects

hg38 • Region Span ~4.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

agammaglobulinemia 3, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013288

Submitter: Labcorp Genetics (formerly Invitae)

agammaglobulinemia 3, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013288

Submitter: Ambry Genetics

autosomal agammaglobulinemiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011096

Submitter: Orphanet

agammaglobulinemia 3, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013288

Submitter: ClinGen

CD79A was first reported in relation to autosomal recessive agammaglobulinemia 3 in 1999 (Minegishi Y, et al., 1999; PMID: 10525050). CD79A encodes Igα, which is part of the B-cell antigen receptor (BCR) complex and is required, in cooperation with Igβ, for initiation of the signal transduction cascade. Agammaglobulinemia 3 is a primary immunodeficiency characterized by profoundly low or absent serum immunoglobulins and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals are susceptible to recurrent infections. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. The mechanism of disease is homozygous loss of function and seven unique variants have been reported in humans, including nonsense, frameshift, and splicing. Variants in this gene have been reported in at least 7 probands in 6 publications (PMIDs: 11920841, 10525050, 29335801, 24481606, 19302039, 31696364), and segregated with disease in one additional family member (PMID: 31696364). Experimentally, this gene-disease relationship is supported by its expression in B cells (PMID: 1729378), its role in BCR signal transduction (PMID: 7688784), which is altered in patient cells (PMID: 10525050), and its interaction with BLNK in the signaling pathway (PMID: 11909947). Further support is provided by at least two mouse models (PMIDs: 8650582, 12097390), which recapitulate features of agammaglobulinemia. In summary CD79A is definitively associated with autosomal recessive agammaglobulinemia 3. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Clinical Genomic Database (CGD)

Agammaglobulinemia 3, autosomal recessiveAR

Manifestation: Allergy/Immunology/Infectious

Intervention: Allergy/Immunology/Infectious

Rationale: Antiinfectious prophylaxis and early and aggressive treatment of infections may be beneficial

Refs: 10525050; 11920841

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CD79A variants in ClinVar

6 Conditions Cataloged

Agammaglobulinemia 3, autosomal recessiveTotal: 161

not specifiedTotal: 37

not providedTotal: 18

CD79A-related disorderTotal: 4

Inherited Immunodeficiency DiseasesTotal: 1

Autosomal recessive agammaglobulinemia 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001783.4. 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				53 clinvar		53
missense	1 clinvar		75 clinvar	7 clinvar		83
nonsense	2 clinvar		1 clinvar			3
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)	2 clinvar	2 clinvar	1 clinvar			5
Total	6	2	77	60	0	145

Highest pathogenic variant AF is 0.0000061681603

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001783.4	RefSeq	NP_001774.1	5	MANE Select
ENST00000221972.8	Ensembl	ENSP00000221972.3	5	MANE Select
NM_021601.4	RefSeq	NP_067612.1	5	Standard
ENST00000444740.2	Ensembl	ENSP00000400605.1	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Primary immunodeficiency - Homo sapiens (human)
B cell receptor signaling pathway - Homo sapiens (human)
B Cell Receptor Signaling Pathway
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers
bcr signaling pathway

Biological Process

adaptive immune response
B cell differentiation
B cell proliferation
B cell activation
B cell receptor signaling pathway

Molecular Function

transmembrane signaling receptor activity
protein binding
protein homodimerization activity

Cellular Component

multivesicular body
plasma membrane
external side of plasma membrane
integral component of membrane
B cell receptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000221972
Coding exons: 5
Length: 4250
Individuals with no LoFs: 125720
Homozygous LoFs: 0
Heterozygous LoFs: 8
Defined: 125728
p: 0.0000318

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.13	100	137	0.729	0.00000886	1457
Missense (PolyPhen)		28	50.383	0.55575		533
Synonymous	1.08	53	64.0	0.828	0.00000496	441
Loss of Function	2.76	2	12.5	0.159	7.84e-7	112

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00014	0.00012	rare
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000036	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required in cooperation with CD79B for initiation of the signal transduction cascade activated by binding of antigen to the B-cell antigen receptor complex (BCR) which leads to internalization of the complex, trafficking to late endosomes and antigen presentation. Also required for BCR surface expression and for efficient differentiation of pro- and pre-B-cells. Stimulates SYK autophosphorylation and activation. Binds to BLNK, bringing BLNK into proximity with SYK and allowing SYK to phosphorylate BLNK. Also interacts with and increases activity of some Src- family tyrosine kinases. Represses BCR signaling during development of immature B-cells. {ECO:0000269|PubMed:8617796, ECO:0000269|PubMed:9057631}.;
Disease: DISEASE: Agammaglobulinemia 3, autosomal recessive (AGM3) [MIM:613501]: A primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life. {ECO:0000269|PubMed:10525050, ECO:0000269|PubMed:11920841}. Note=The disease is caused by mutations affecting the gene represented in this entry. Two different mutations, one at the splice donor site of intron 2 and the other at the splice acceptor site for exon 3, have been identified. Both mutations give rise to a truncated protein.;

Intolerance Scores

LoFtool: 0.258
RVIS EVS: 0.13
RVIS percentile EVS: 63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.874

Gene Damage Prediction

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