RFX3

Chr 9

regulatory factor X3

NCBI Gene: 5991 ENSG00000080298 UniProt: P48380 OMIM: 601337

The protein encoded by RFX3 is a transcription factor essential for ciliogenesis, regulating genes involved in ciliary assembly and motility, and also required for islet cell differentiation during pancreatic development. Mutations cause autosomal recessive primary ciliary dyskinesia with situs inversus and pancreatic islet cell dysfunction. The disorder affects respiratory function due to impaired ciliary motility and can involve laterality defects and endocrine pancreatic abnormalities.

OMIM ResearchSummary from RefSeq, UniProt

This gene is a member of the regulatory factor X gene family, which encodes transcription factors that contain a highly-conserved winged helix DNA binding domain. The protein encoded by this gene is structurally related to regulatory factors X1, X2, X4, and X5. It is a transcriptional activator that can bind DNA as a monomer or as a heterodimer with other RFX family members. Multiple transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2013]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.10

Clinical Summary— RFX3

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Gene-Disease Validity (ClinGen)

complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

12 unique Pathogenic / Likely Pathogenic· 101 VUS of 153 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.10LOEUF

pLI 1.000

Z-score 6.14

OE 0.02 (0.01–0.10)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.47Z-score

OE missense 0.53 (0.47–0.59)

223 obs / 424.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.10)

0≤0.351.4

Missense OE?0.53 (0.47–0.59)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 1 / 45.8Missense obs/exp: 223 / 424.3Syn Z: -2.11

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRFX3-related neurodevelopmental disorder with autism and other behavioural abnormalitiesLOFAD

This gene — mechanism propensity

0.3196th %ile

GOF

0.3392th %ile

LOF

0.77top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 83% of P/LP variants are LoF · LOEUF 0.10 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

153 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic9

VUS101

Likely Benign21

Benign4

Conflicting2

Pathogenic

Likely Pathogenic

101

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	0	0	0	3
Likely Pathogenic	7	1	1	0	9
VUS	6	90	5	0	101
Likely Benign	0	8	3	10	21
Benign	0	0	1	3	4
Conflicting	—				2
Total	16	99	10	13	140

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

View in ClinVar →

176 pathogenic / likely-pathogenic (of 196) ClinVar copy-number / structural variants overlap RFX3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →