RFXANK

protein-coding

regulatory factor X associated ankyrin containing protein, the group of Ankyrin repeat domain containing

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 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. This protein contains ankyrin repeats involved in protein-protein interactions. Mutations in this gene have been linked to bare lymphocyte syndrome type II, complementation group B. Multiple alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jul 2013]

MANE transcript

NM_003721.4

Inheritance

ClinVar variants

P:36U:110B:94

Top phenotype

MHC class II deficiency

gnomAD constraint

pLI —, LoF o/e 0.66

Max pathogenic AF

—

Genomic locus

chr19:19,192,229-19,201,869

External References & Databases

Ensembl (ENSG00000064490)

Transcript & Mutation Effects

hg38 • Region Span ~9.6 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: ClinGen

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 genes CIITA, RFXANK, RFX5, and RFXAP are responsible for the primary immunodeficiency. At least 19 total variants, including (nonsense, missense, and splice site) have been reported. Affected individuals typically present in infancy with severe, recurrent infections, diarrhea, failure to thrive, low levels of CD4+ T cells, and undetectable HLA-DR expression on monocytes and B cells. Heterozygous carriers of RFXANK variants are reportedly unaffected clinically. The mechanism of pathogenicity appears to be loss of function. One variant, c.752delG26bp, has been reported in over 50 individuals (PMID:32875002). Individuals who are homozygous for the variant display combined immudeficiency, MHC class two defieincy, and die early in life if left untreated. Nearly all probands reported with the mutation are from the Maghreb region in North Africa. One paper, PMID:21908431, estimated that the variant originated with a founder from ∼2250 years ago (95% CI: 1700-3025 years) in what was most likely an ancient Berber civilization. This gene-disease association is supported by experimental evidence including RFXANK co-immunoprecipitation with CIITA (PMID:11463838), rescue of function in patient cells (PMID:11313409), and biochemical function (PMID:18723135). In summary, RFXANK 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. Classification approved by SCID-CID GCEP on 11/17/2022.

MHC class II deficiency 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0971013

Submitter: PanelApp Australia

MHC class II deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008855

Submitter: Labcorp Genetics (formerly Invitae)

MHC class II deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008855

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

Clinical Genomic Database (CGD)

MHC class II deficiencyAR

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: 7951244; 9806546; 11313409; 12618906; 20414676; 21908431

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RFXANK variants in ClinVar

10 Conditions Cataloged

MHC class II deficiencyTotal: 277

Inborn genetic diseasesTotal: 45

not specifiedTotal: 25

not providedTotal: 21

MHC class II deficiency 2Total: 19

RFXANK-related disorderTotal: 9

MHC class II deficiency 1Total: 5

MHC class II deficiency 5Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003721.4. 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				84 clinvar		84
missense		3 clinvar	105 clinvar	9 clinvar	1 clinvar	118
nonsense	5 clinvar	4 clinvar	1 clinvar			10
start loss						0
frameshift	7 clinvar	6 clinvar				13
splice donor/acceptor (+/-2bp)	3 clinvar	8 clinvar	4 clinvar			15
Total	15	21	110	93	1	240

Highest pathogenic variant AF is 0.000014921736

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 74 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003721.4	RefSeq	NP_003712.1	8	MANE Select
ENST00000303088.9	Ensembl	ENSP00000305071.2	8	MANE Select
NM_001278727.2	RefSeq	NP_001265656.1	7	Standard
NM_001278728.2	RefSeq	NP_001265657.1	7	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)
Signaling events mediated by HDAC Class II

Biological Process

Ras protein signal transduction
positive regulation of transcription by RNA polymerase II

Molecular Function

DNA binding
DNA-binding transcription factor activity
transcription coregulator activity
histone deacetylase binding

Cellular Component

nucleus
nucleoplasm
cytosol
intercellular bridge

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000303088
Coding exons: 8
Length: 9671
Individuals with no LoFs: 125706
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 125748
p: 0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.266	145	154	0.940	0.0000108	1658
Missense (PolyPhen)		48	54.582	0.8794		562
Synonymous	-0.794	79	70.5	1.12	0.00000572	555
Loss of Function	1.23	10	15.1	0.660	9.31e-7	148

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00020	0.00020	rare
South Asian	0.000098	0.000098	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Activates transcription from class II MHC promoters. Activation requires the activity of the MHC class II transactivator/CIITA. May regulate other genes in the cell. RFX binds the X1 box of MHC-II promoters (PubMed:9806546, PubMed:10072068, PubMed:10725724). May also potentiate the activation of RAF1 (By similarity). {ECO:0000250|UniProtKB:Q9Z205, ECO:0000269|PubMed:10072068, ECO:0000269|PubMed:10725724, ECO:0000269|PubMed:9806546}.;
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:10725724, ECO:0000269|PubMed:22649097, ECO:0000269|PubMed:9806546}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.232

Intolerance Scores

LoFtool: 0.845
RVIS EVS: 0.31
RVIS percentile EVS: 72.38

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.908

Gene Damage Prediction

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