RBFOX2

protein-coding

RNA binding fox-1 homolog 2, the group of RNA binding motif containing

Gene summary

This gene is one of several human genes similar to the C. elegans gene Fox-1. This gene encodes an RNA binding protein that is thought to be a key regulator of alternative exon splicing in the nervous system and other cell types. The protein binds to a conserved UGCAUG element found downstream of many alternatively spliced exons and promotes inclusion of the alternative exon in mature transcripts. The protein also interacts with the estrogen receptor 1 transcription factor and regulates estrogen receptor 1 transcriptional activity. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

RBM9

MANE transcript

NM_001349999.2

Inheritance

ClinVar variants

P:5U:74B:38

Top phenotype

congenital heart defects, multiple types

gnomAD constraint

pLI —, LoF o/e 0.04

Max pathogenic AF

—

Genomic locus

chr22:35,738,736-36,028,824

External References & Databases

Ensembl (ENSG00000100320)

Transcript & Mutation Effects

hg38 • Region Span ~290.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital heart defects, multiple typesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0000119

Submitter: Ambry Genetics

congenital heart diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0005453

Submitter: ClinGen

*RBFOX2* was first reported in relation to autosomal dominant congenital heart disease in 2015 (Homsy et al., PMID: 26785492). At least 5 rare variants (1 missense, 4 loss-of-function) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. *RBFOX2* has been noted to be associated with the following disease entities: aortic stenosis/atresia, atrial septal defects, double outlet right ventricle, hypoplastic aortic arch, and hypoplastic left ventricle (OMIM 619657). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern. Therefore, these disease entities have been lumped into one disease entity, Autosomal Dominant RBFOX2-related Congenital Heart Disorders. Variants in this gene have been reported in at least 5 probands in 2 publications from the same research consortium (PMIDs 26785492, 28991257), using an allele frequency threshold of 1x10-5. This gene-disease relationship is supported by animal models, expression studies, and functional assays. Expression studies confirmed that *RBFOX2* is expressed during zebrafish embryogenesis (PMID 21925157), mouse embryogenesis (PMID 31241461) and in rat cardiac myoblasts (PMID 24151077). Depletion of Rbfox2 in rat cardiac myoblasts mouse cardiomyocytes led to aberrant splicing of target mRNAs (PMIDs 31241461, 31778749). Multiple zebrafish models demonstrated abnormal cardiac development after depletion of rbfox2 and rbfox1l, with rescue of the ventricular hypoplasia after introduction of rbfox2 mRNA (PMIDs 21925157, 36198703). Mouse embryos deficient for Rbfox2 resulted in thin ventricular walls (PMID 35137168). In summary, there is strong evidence to support this gene-disease relationship. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 3/5/24 (SOP Version 10).

RBFOX2-related congenital heart disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0100557

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RBFOX2 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 74

Inborn genetic diseasesTotal: 51

RBFOX2-related conditionTotal: 3

RBFOX2-related congenital heart disorderTotal: 2

Congenital heart diseaseTotal: 1

not specifiedTotal: 1

Congenital heart defectTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001349999.2. 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				31 clinvar	5 clinvar	36
missense	1 clinvar		67 clinvar	1 clinvar	1 clinvar	70
nonsense	1 clinvar	2 clinvar				3
start loss			1 clinvar			1
frameshift	1 clinvar		2 clinvar			3
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	3	2	74	32	6	117

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 133 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001349999.2	RefSeq	NP_001336928.2	14	MANE Select
ENST00000695854.1	Ensembl	ENSP00000512219.1	14	MANE Select
NM_001031695.4	RefSeq	NP_001026865.1	13	Standard
NM_001082576.3	RefSeq	NP_001076045.1	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
rbfox2	Danio rerio	Structure: skeletal muscle Quality: decreased force abnormal

Gene / Model

Organism

Observed Phenotype

rbfox2

Danio rerio

Structure: skeletal muscle

Quality: decreased force

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

FGFR2 alternative splicing
Signaling by FGFR2
Signal Transduction
Signaling by FGFR
Signaling by Receptor Tyrosine Kinases

Biological Process

regulation of alternative mRNA splicing, via spliceosome
mRNA processing
nervous system development
RNA splicing
fibroblast growth factor receptor signaling pathway

Molecular Function

transcription corepressor activity
RNA binding
mRNA binding
protein binding
transcription factor binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000438146
Coding exons: 14
Length: 289691
Individuals with no LoFs: 124485
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 124486
p: 0.00000402

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.58	144	262	0.550	0.0000161	2844
Missense (PolyPhen)		39	119.69	0.32584		1201
Synonymous	-0.278	109	105	1.03	0.00000720	935
Loss of Function	4.40	1	24.5	0.0408	0.00000121	293

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: RNA-binding protein that regulates alternative splicing events by binding to 5'-UGCAUGU-3' elements. Prevents binding of U2AF2 to the 3'-splice site. Regulates alternative splicing of tissue-specific exons and of differentially spliced exons during erythropoiesis (By similarity). RNA-binding protein that seems to act as a coregulatory factor of ER-alpha. {ECO:0000250, ECO:0000269|PubMed:11875103}.;

Recessive Scores

pRec: 0.0922

Intolerance Scores

RVIS EVS: -0.43
RVIS percentile EVS: 25.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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