RFX5

protein-coding

regulatory factor X5, the group of Regulatory factor X family

Gene summary

A lack of MHC-II expression results in a severe immunodeficiency syndrome called MHC-II deficiency, or the bare lymphocyte syndrome (BLS; MIM 209920). At least 4 complementation groups have been identified in B-cell lines established from patients with BLS. The molecular defects in complementation groups B, C, and D all lead to a deficiency in RFX, a nuclear protein complex that binds to the X box of MHC-II promoters. The lack of RFX binding activity in complementation group C results from mutations in the RFX5 gene encoding the 75-kD subunit of RFX (Steimle et al., 1995). RFX5 is the fifth member of the growing family of DNA-binding proteins sharing a novel and highly characteristic DNA-binding domain called the RFX motif. Multiple alternatively spliced transcript variants have been found but the full-length natures of only two have been determined. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001025603.2

Inheritance

ClinVar variants

P:50U:236B:101

Top phenotype

MHC class II deficiency 3; MHC class II deficiency 5

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr1:151,340,640-151,347,326

External References & Databases

Ensembl (ENSG00000143390)

Transcript & Mutation Effects

hg38 • Region Span ~6.7 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 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008855

Submitter: Ambry Genetics

MHC class II deficiency 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0971014

Submitter: PanelApp Australia

MHC class II deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008855

Submitter: Labcorp Genetics (formerly Invitae)

MHC class II deficiency 5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0971016

Submitter: PanelApp Australia

MHC class II deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008855

Submitter: ClinGen

*RFX5* was first reported in relation to autosomal recessive major histocompatibility complex (MHC) class II deficiency in 1995 (Steimle V, et al., 1995, PMID: 7744245 ). MHC class II molecules are essential for the presentation of exogenous peptides to CD4+ helper T cells and thus in the adaptive immune response. Mutations in four trans-acting genes *CIITA,* *RFXANK,* *RFX5,* and *RFXAP* are responsible for the primary immunodeficiency. Pathogenic variants in RFX5 are associated with BLS complementation group C.Affected individuals typically present in infancy with severe, recurrent infections, failure to thrive, low levels of CD4+ T cells, and undetectable undetectable MHC class II (e.g., HLA DR) expression on monocytes and B cells. The mechanism of pathogenicity appears to be bialleleic loss of function. Heterozygous carriers of *RFX5* loss of function variants are not reported to be clinically affected. The *RFX5* curation includes 8 variants (frameshift, nonsense, missense, and splice site) reported in 8 probands from 6 publications (PMIDs: 7744245, 9401005, 10079298, 12368908, 30084052, 29527204). Additional evidence is available however the maximum score for genetic evidence was reached. This gene-disease association is supported by experimental evidence including its biochemical function, as part of the RFX complex, of binding DNA in a X1-box-spiceifc manner to allow for transcriptional activation of MHC class II molecules (PMID: 10938133). The MHC class II deficiency can be rescued in patient cells by expression of wildtype *RFX5* (PMID: 7744245 ). Furthermore, it interacts with the transactivator *CIITA,* which is also implicated in MHC class II deficiency (PMID: 10938133). Additionally, RFX5−/− mice exhibit an immune deficiency that is very similar to that of MHC-II–deficient patients (PMID: 9491996). In summary, *RFX5* is definitively associated with autosomal recessive MHC class II deficiency. This has been repeatedly demonstrated in both research and the clinical diagnostic setting and has been upheld over time.

Clinical Genomic Database (CGD)

MHC class II deficiency 3; MHC class II deficiency 5AR

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: 7744245; 9401005; 10079298; 12368908

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RFX5 variants in ClinVar

7 Conditions Cataloged

MHC class II deficiencyTotal: 379

not specifiedTotal: 128

not providedTotal: 45

MHC class II deficiency 3Total: 12

RFX5-related disorderTotal: 12

MHC class II deficiency 5Total: 4

MHC class II deficiency 1Total: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001025603.2. 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	90 clinvar		93
missense		1 clinvar	223 clinvar	11 clinvar		235
nonsense	8 clinvar	3 clinvar	1 clinvar			12
start loss						0
frameshift	18 clinvar	6 clinvar	5 clinvar			29
splice donor/acceptor (+/-2bp)	3 clinvar	11 clinvar	4 clinvar			18
Total	29	21	236	101	0	387

Highest pathogenic variant AF is 0.00018071439

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 59 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001025603.2	RefSeq	NP_001020774.1	9	MANE Select
ENST00000452671.7	Ensembl	ENSP00000389130.2	9	MANE Select
NM_000449.4	RefSeq	NP_000440.1	9	Standard
NM_001379412.1	RefSeq	NP_001366341.1	9	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)
Prion disease pathway

Biological Process

negative regulation of transcription by RNA polymerase II
regulation of transcription by RNA polymerase II
positive regulation of transcription by RNA polymerase II

Molecular Function

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

Cellular Component

nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000290524
Coding exons: 9
Length: 6718
Individuals with no LoFs: 125682
Homozygous LoFs: 0
Heterozygous LoFs: 66
Defined: 125748
p: 0.000262

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.476	314	339	0.927	0.0000198	3915
Missense (PolyPhen)		92	111.4	0.82589		1248
Synonymous	2.23	95	127	0.748	0.00000661	1348
Loss of Function	1.14	20	26.3	0.760	0.00000183	299

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00044	0.00043	rare
Latino/Admixed American	0.00023	0.00023	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.0011	0.0011	notable
European (Non-Finnish)	0.00015	0.00015	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Activates transcription from class II MHC promoters. Recognizes X-boxes. Mediates cooperative binding between RFX and NF-Y. RFX binds the X1 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:10825209}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.137

Intolerance Scores

LoFtool: 0.506
RVIS EVS: 0.04
RVIS percentile EVS: 57.41

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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