RNF43

protein-coding

ring finger protein 43, the group of Ring finger proteins

Gene summary

The protein encoded by this gene is a RING-type E3 ubiquitin ligase and is predicted to contain a transmembrane domain, a protease-associated domain, an ectodomain, and a cytoplasmic RING domain. This protein is thought to negatively regulate Wnt signaling, and expression of this gene results in an increase in ubiquitination of frizzled receptors, an alteration in their subcellular distribution, resulting in reduced surface levels of these receptors. Mutations in this gene have been reported in multiple tumor cells, including colorectal and endometrial cancers. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]

MANE transcript

NM_017763.6

Inheritance

ClinVar variants

P:59U:866B:478

Top phenotype

Sessile serrated polyposis cancer syndrome

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr17:58,353,676-58,417,595

External References & Databases

Ensembl (ENSG00000108375)

Transcript & Mutation Effects

hg38 • Region Span ~63.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

sessile serrated polyposis cancer syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014919

Submitter: Genomics England PanelApp

hyperplastic polyposis syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015524

Submitter: Orphanet

sessile serrated polyposis cancer syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014919

Submitter: Ambry Genetics

sessile serrated polyposis cancer syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014919

Submitter: ClinGen

RNF43 was first reported in relation to autosomal dominant sessile serrated polyposis (SPS) cancer syndrome in 2014 (Gala et al., PMID: 24512911). SPS is a rare, genetic intestinal disease characterized by the presence of multiple (usually large) serrated colorectal polyps, associated with an increased personal and familial risk of colorectal cancer. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found only one disease entity associated with this gene [Sessile serrated polyposis cancer syndrome] (OMIM:617108). Seven variants (missense, nonsense, frameshift, splice site) that have been reported in nine probands in seven publications (PMIDs: 27081527, 27329244, 27582512, 29330307, 35128723, 34541672, 34761457) are included in this curation (10.7 points). The mechanism of pathogenicity is reported to be heterozygous LOF. This gene-disease relationship is also supported by experimental evidence (3.6 points from animal model, expression studies, in vitro functional assays and second hits in patients' cells) (PMIDs: 18313049, 22895187, 26350900, 27329244, 32934222). Experimental evidence shows that RNF43 is an E3 ubiquitin ligase that negatively regulates Wnt signaling by inducing degradation of the Wnt receptor Frizzled, impacting intestinal cell proliferation. In summary, there is definitive evidence to support the relationship between RNF43 and autosomal dominant sessile serrated polyposis cancer syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

sessile serrated polyposis cancer syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014919

Submitter: Ambry Genetics

sessile serrated polyposis cancer syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0014919

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Sessile serrated polyposis cancer syndromeAD

Manifestation: Oncologic

Intervention: Oncologic

Rationale: Individuals are at high risk of developing colorectal cancer (and possibly additional neoplasms), and awareness may allow surveillance and early surgical and medical management of neoplasms

Refs: 24512911; 27081527

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RNF43 variants in ClinVar

9 Conditions Cataloged

not specifiedTotal: 1167

not providedTotal: 691

Sessile serrated polyposis cancer syndromeTotal: 454

Hyperplastic polyposis syndromeTotal: 33

RNF43-related disorderTotal: 18

Hereditary cancer-predisposing syndromeTotal: 10

Inherited polyposis and early onset colorectal cancer - germline testingTotal: 4

Colon serrated polyposisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_017763.6. 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			6 clinvar	350 clinvar	40 clinvar	396
missense			818 clinvar	83 clinvar	5 clinvar	906
nonsense	9 clinvar	17 clinvar	13 clinvar			39
start loss						0
frameshift	13 clinvar	13 clinvar	21 clinvar			47
splice donor/acceptor (+/-2bp)		7 clinvar	8 clinvar			15
Total	22	37	866	433	45	1403

Highest pathogenic variant AF is 0.000024187757

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_017763.6	RefSeq	NP_060233.3	9	MANE Select
ENST00000407977.7	Ensembl	ENSP00000385328.2	9	MANE Select
NM_001305544.3	RefSeq	NP_001292473.1	9	Standard
NM_001305545.2	RefSeq	NP_001292474.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signaling by WNT
Signal Transduction
p73 transcription factor network
Regulation of FZD by ubiquitination
TCF dependent signaling in response to WNT

Biological Process

ubiquitin-dependent protein catabolic process
multicellular organism development
Wnt signaling pathway
protein ubiquitination
negative regulation of Wnt signaling pathway

Molecular Function

ubiquitin-protein transferase activity
frizzled binding
protein binding
metal ion binding
ubiquitin protein ligase activity

Cellular Component

nuclear envelope
endoplasmic reticulum membrane
plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000584437
Coding exons: 9
Length: 65096
Individuals with no LoFs: 125726
Homozygous LoFs: 0
Heterozygous LoFs: 21
Defined: 125747
p: 0.0000835

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.85	339	449	0.754	0.0000261	4982
Missense (PolyPhen)		87	150.41	0.5784		1773
Synonymous	1.08	156	174	0.896	0.00000915	1678
Loss of Function	4.40	7	35.1	0.199	0.00000206	339

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00018	0.00017	rare
Ashkenazi Jewish	0.00011	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000088	0.000088	rare
South Asian	0.000069	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase that acts as a negative regulator of the Wnt signaling pathway by mediating the ubiquitination, endocytosis and subsequent degradation of Wnt receptor complex components Frizzled. Acts on both canonical and non-canonical Wnt signaling pathway. Acts as a tumor suppressor in the intestinal stem cell zone by inhibiting the Wnt signaling pathway, thereby resticting the size of the intestinal stem cell zone. {ECO:0000269|PubMed:18313049, ECO:0000269|PubMed:22575959, ECO:0000269|PubMed:22895187}.;
Disease: DISEASE: Sessile serrated polyposis cancer syndrome (SSPCS) [MIM:617108]: A rare disease characterized by multiple and/or large serrated polyps developing in the colon, and an increased personal and familial risk of colorectal cancer. A patient is diagnosed with SSPCS if at least one of the following criteria is met: the presence of at least five sessile serrated polyps proximal to the sigmoid colon, two of which are greater than 10 mm in diameter; the presence of any number of serrated polyps occurring proximal to the sigmoid colon in an individual who has a first-degree relative with serrated polyposis; the presence of more than 20 serrated polyps of any size distributed throughout the colon. Sessile serrated polyps are also known as sessile serrated adenomas (SSA) and are estimated to be responsible for 20 to 35% of all colon cancers. Individuals with SSPCS may have a strong personal or family history of extracolonic cancers. {ECO:0000269|PubMed:24512911, ECO:0000269|PubMed:27081527}. Note=Disease susceptibility may be associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0897

Intolerance Scores

LoFtool: 0.632
RVIS EVS: 0.74
RVIS percentile EVS: 86.33

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.910

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High