RFX5

Chr 1AR

regulatory factor X5

Also known as: MHC2D3, MHC2D5

NCBI Gene: 5993 ENSG00000143390 UniProt: P48382 OMIM: 601863

RFX5 encodes the 75-kD subunit of RFX, a nuclear protein complex that activates transcription from MHC class II promoters by binding to X-boxes in the promoter regions. Mutations cause MHC class II deficiency (bare lymphocyte syndrome), an autosomal recessive severe combined immunodeficiency presenting in early infancy with recurrent infections due to absent MHC class II expression on immune cells. The gene shows very low constraint against loss-of-function variants (pLI near zero), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

ARLOEUF 1.102 OMIM phenotypes

Clinical Summary— RFX5

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Gene-Disease Validity (ClinGen)

MHC class II deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

51 unique Pathogenic / Likely Pathogenic· 250 VUS of 475 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.10LOEUF

pLI 0.000

Z-score 1.14

OE 0.76 (0.53–1.10)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.48Z-score

OE missense 0.93 (0.84–1.02)

314 obs / 338.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.76 (0.53–1.10)

0≤0.351.4

Missense OE?0.93 (0.84–1.02)

0≤0.61.4

Synonymous OE?0.75

0≤1.21.6

LoF obs/exp: 20 / 26.3Missense obs/exp: 314 / 338.7Syn Z: 2.23

ClinVar Variant Classifications

475 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31

Likely Pathogenic20

VUS250

Likely Benign140

Benign9

Conflicting11

Pathogenic

Likely Pathogenic

250

VUS

140

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	30	0	1	0	31
Likely Pathogenic	19	1	0	0	20
VUS	6	218	25	1	250
Likely Benign	0	6	50	84	140
Benign	0	1	6	2	9
Conflicting	—				11
Total	55	226	82	87	461

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

15 pathogenic / likely-pathogenic (of 20) ClinVar copy-number / structural variants overlap RFX5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →