RFXAP

protein-coding

regulatory factor X associated protein

Gene summary

Major histocompatibility (MHC) class II molecules are transmembrane proteins that have a central role in development and control of the immune system. The protein encoded by this gene, along with regulatory factor X-associated ankyrin-containing protein and regulatory factor-5, forms a complex that binds to the X box motif of certain MHC class II gene promoters and activates their transcription. Once bound to the promoter, this complex associates with the non-DNA-binding factor MHC class II transactivator, which controls the cell type specificity and inducibility of MHC class II gene expression. Mutations in this gene have been linked to bare lymphocyte syndrome type II, complementation group D. Transcript variants utilizing different polyA signals have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_000538.4

Inheritance

ClinVar variants

P:30U:98B:56

Top phenotype

MHC class II deficiency 4

gnomAD constraint

pLI —, LoF o/e 0.43

Max pathogenic AF

—

Genomic locus

chr13:36,819,222-36,829,104

External References & Databases

Ensembl (ENSG00000133111)

Transcript & Mutation Effects

hg38 • Region Span ~9.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

MHC class II deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008855

Submitter: Orphanet

MHC class II deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008855

Submitter: Labcorp Genetics (formerly Invitae)

MHC class II deficiency 4STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0971015

Submitter: PanelApp Australia

MHC class II deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008855

Submitter: ClinGen

RFXAP- Type II Vare Lymphocyte Syndrome Biallelic RFXAP germline variants were first reported in relationship to type II bare lymphocytes syndrome (BLS) in 1997 (PMID: 9118943, 9287230). Pathogenic variants in RFXAP are associated with BLS complementation group D. Patients with BLS exhibit opportunistic infections, failure to thrive, reduced class-switched antibody levels and reduced CD4 T cell numbers. Nine variants were curated and are composed of frameshift, nonsense, splice site and promoter variants causing the silence of gene expression. Evidence supporting this gene-disease relationship includes case-level and experimental data. Heterozygous carriers have not been shown to have a clinical phenotype. The maximum score for genetic evidence has been reached (12 pts) for this curation. RFXAP is one of four trans-acting regulatory factors that are required for the transcription of major histocompatibility complex class II (MHC class II) genes. RFXAP is a component of the RFX complex, which is composed of RFXAP, RFX5 and RFXANK. The RFX complex binds to the MHC class II promoter, promotes the assembly of other components of the MHC class II enhanceosome and initiates transcription of MHC class II genes (PMID: 9118943, 19274739, 16337482). MHC class II plays an essential role in the development, maintenance, and activation of CD4+ T cells. As such, patients with BLS exhibit significant defects in CD4+ T cell development and function. In summary, there is definitive evidence to support this gene-disease relationship. This association 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 Working Group on 6/15/2023 (SOP Version 9). Biocurator:Ryan Martinez Expert:Miao Sun

Clinical Genomic Database (CGD)

MHC class II deficiency 4AR

Manifestation: Allergy/Immunology/Infectious; Gastrointestinal

Intervention: Allergy/Immunology/Infectious

Rationale: Prophylaxis and early and aggressive treatment of infections can be beneficial; BMT has been reported in Bare lymphocyte syndrome, type II

Refs: 650344; 7021490; 9118943; 20197681

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RFXAP variants in ClinVar

7 Conditions Cataloged

MHC class II deficiencyTotal: 165

not specifiedTotal: 50

not providedTotal: 18

MHC class II deficiency 4Total: 15

RFXAP-related disorderTotal: 2

MHC class II deficiency 1Total: 2

Primary ciliary dyskinesiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000538.4. 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			3 clinvar	52 clinvar		55
missense			90 clinvar	4 clinvar		94
nonsense	5 clinvar	3 clinvar	1 clinvar			9
start loss			1 clinvar			1
frameshift	15 clinvar	5 clinvar	3 clinvar			23
splice donor/acceptor (+/-2bp)		2 clinvar				2
Total	20	10	98	56	0	184

Highest pathogenic variant AF is 0.00003110936

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000538.4	RefSeq	NP_000529.1	3	MANE Select
ENST00000255476.3	Ensembl	ENSP00000255476.3	3	MANE Select
ENST00001123459.1	Ensembl	ENSP00000793264.1	2	Standard
ENST00001123460.1	Ensembl	ENSP00000793265.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Antigen processing and presentation - Homo sapiens (human)
Primary immunodeficiency - Homo sapiens (human)
Tuberculosis - Homo sapiens (human)

Biological Process

positive regulation of transcription, DNA-templated

Molecular Function

DNA binding
DNA-binding transcription factor activity
transcription coactivator activity

Cellular Component

nucleus
nuclear speck

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000255476
Coding exons: 3
Length: 9881
Individuals with no LoFs: 124965
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 124967
p: 0.00000800

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.04	99	133	0.747	0.00000607	1730
Missense (PolyPhen)		41	54.681	0.7498		697
Synonymous	0.193	52	53.8	0.967	0.00000249	542
Loss of Function	1.62	4	9.36	0.427	3.97e-7	118

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
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)	0.0000096	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Part of the RFX complex that binds to the X-box of MHC II promoters.;
Disease: DISEASE: Bare lymphocyte syndrome 2 (BLS2) [MIM:209920]: A severe combined immunodeficiency disease with early onset. It is characterized by a profound defect in constitutive and interferon- gamma induced MHC II expression, absence of cellular and humoral T-cell response to antigen challenge, hypogammaglobulinemia and impaired antibody production. The consequence include extreme susceptibility to viral, bacterial and fungal infections. {ECO:0000269|PubMed:10072068, ECO:0000269|PubMed:9118943}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.114

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.463

Gene Damage Prediction

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