GeneBe

RFX3

protein-coding

regulatory factor X3, the group of Regulatory factor X family

Gene summary

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]

MANE transcript

NM_001282116.2

Inheritance

AD

ClinVar variants

P:14U:115B:21

Top phenotype

complex neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr9:3,218,297-3,526,004

External References & Databases

Ensembl (ENSG00000080298)NCBI Gene (5991)OMIM (601337)HGNC:9984GenCCUniProt (P48380)AlphaFoldClinVar (RFX3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~307.7 kb
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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

Although *de novo* single gene deletions and protein truncating variants in *RFX3* had been reported in individuals with developmental delay, intellectual disability (ID), and autism spectrum disorder (ASD) as early as 2011 (PMIDs: 21792059, 27525107, 31981491), the first report focusing on variants in *RFX3* in relation to autosomal dominant complex neurodevelopmental disorder was published in 2021 (Harris et al., PMID: 33658631). *RFX3* encodes a member of the regulatory factor X (RFX) family of genes that act as master regulators of central nervous system development and ciliogenesis. Eight unique variants (2 nonsense, 3 frameshift, 1 canonical splice site, 1 multi-exon deletion, and 1 full gene deletion) reported in 8 probands in 4 publications (PMIDs: 25844147, 27525107, 31981491, 33658631) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Most reported variants are *de novo*, although one family was reported in which an affected parent transmitted a frameshift variant to three affected children (PMID: 33658631); there are also reports of inherited deletions (PMID: 21792059) and protein truncating variants (PMIDs: 25961944, 35982159) in individuals with ASD or ID. The mechanism of disease is suggested to be haploinsufficiency (PMID: 33658631). Three patients with missense or inframe indel variants have also been reported (PMID: 33658631), but were not scored in this curation due to lack of convincing functional data and unclear disease mechanism. *RFX3* is highly constrained for both missense (Z = 3.17, gnomAD v4.0.0) and loss-of-function variants (pLI = 1). There are a limited number of probands with detailed phenotypic features reported. Of those cases, affected individuals present with motor and speech delays, ID, ASD, and behavioral abnormalities; other variable features include attention deficit hyperactivity disorder, dysmorphic features, hypotonia, micro/macrocephaly, seizures, and sleep abnormalities (PMIDs: 25844147, 33658631). This gene-disease relationship is also supported by variants in other RFX genes (*RFX7* and *RFX4*) reported in individuals with global developmental delay, ID and ASD (PMID: 33658631). In summary, there is definitive evidence supporting the relationship between *RFX3* and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on April 3, 2024 (SOP Version 10).

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: G2P

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

complex neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: Ambry Genetics

autism spectrum disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005258

Submitter: Ambry Genetics

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RFX3 variants in ClinVar

13 Conditions Cataloged
not providedTotal: 91
Inborn genetic diseasesTotal: 48
RFX3-related disorderTotal: 28
Neurodevelopmental disorderTotal: 3
RFX3-related neurodevelopmental disorder with autism and other behavioural abnormalitiesTotal: 2
not specifiedTotal: 2
RFX3-related intellectual disabilityTotal: 1
Autism spectrum disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001282116.2. 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.

EffectPLPVUSLBBSum
synonymous
1
clinvar
12
clinvar
2
clinvar
 15
missense
1
clinvar
106
clinvar
7
clinvar
 114
nonsense
3
clinvar
1
clinvar
2
clinvar
 6
start loss
0
frameshift
6
clinvar
3
clinvar
 9
splice donor/acceptor (+/-2bp)
3
clinvar
3
clinvar
 6
Total311115192150

Highest pathogenic variant AF is 6.8439994e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 63 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001282116.2RefSeqNP_001269045.116MANE Select
ENST00000617270.5EnsemblENSP00000482598.116MANE Select
NM_001282117.2RefSeqNP_001269046.19Standard
NM_001377999.1RefSeqNP_001364928.117Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

  • transcription, DNA-templated
  • regulation of transcription, DNA-templated
  • regulation of transcription by RNA polymerase II
  • endocrine pancreas development
  • negative regulation of transcription, DNA-templated

Molecular Function

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

Cellular Component

  • nuclear chromatin
  • nucleus
  • transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000382004
Coding exons
16
Length
307708
Individuals with no LoFs
125650
Homozygous LoFs
0
Heterozygous LoFs
4
Defined
125654
p
0.0000159
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.472234240.5260.00002274913
Missense (PolyPhen)18101.850.176731214
Synonymous-2.111931591.210.000009561446
Loss of Function6.14145.80.02180.00000249463

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000180.000018rare
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transcription factor required for ciliogenesis and islet cell differentiation during endocrine pancreas development. Essential for the differentiation of nodal monocilia and left- right asymmetry specification during embryogenesis. Required for the biogenesis of motile cilia by governing growth and beating efficiency of motile cells. Also required for ciliated ependymal cell differentiation. Regulates the expression of genes involved in ciliary assembly (DYNC2LI1, FOXJ1 and BBS4) and genes involved in ciliary motility (DNAH11, DNAH9 and DNAH5) (By similarity). Together with RFX6, participates in the differentiation of 4 of the 5 islet cell types during endocrine pancreas development, with the exception of pancreatic PP (polypeptide-producing) cells. Regulates transcription by forming a heterodimer with another RFX protein and binding to the X-box in the promoter of target genes (PubMed:20148032). Represses transcription of MAP1A in non- neuronal cells but not in neuronal cells (PubMed:12411430). {ECO:0000250|UniProtKB:P48381, ECO:0000269|PubMed:12411430, ECO:0000269|PubMed:20148032}.;

Recessive Scores

pRec
0.140

Intolerance Scores

LoFtool
0.294
RVIS EVS
-0.8
RVIS percentile EVS
12.46

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.969

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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