NM_017763.6:c.350G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_017763.6(RNF43):c.350G>A(p.Arg117His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 1,605,284 control chromosomes in the GnomAD database, including 16,938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.15 ( 1963 hom., cov: 32)

Exomes 𝑓: 0.13 ( 14975 hom. )

Consequence

RNF43
NM_017763.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.00

Variant links:

Genes affected

RNF43 (HGNC:18505): (ring finger protein 43) 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]

RNF43 links:

ENSG00000285897 (HGNC:):

ENSG00000285897 links:

TSPOAP1-AS1 (HGNC:44148): (TSPOAP1, SUPT4H1 and RNF43 antisense RNA 1)

TSPOAP1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032409728).

BP6

Variant 17-58370936-C-T is Benign according to our data. Variant chr17-58370936-C-T is described in ClinVar as [Benign]. Clinvar id is 1165517.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58370936-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF43	NM_017763.6 link	c.350G>A	p.Arg117His	missense_variant	Exon 3 of 10	ENST00000407977.7	NP_060233.3	Q68DV7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF43	ENST00000407977.7 link	c.350G>A	p.Arg117His	missense_variant	Exon 3 of 10	2	NM_017763.6	ENSP00000385328.2		Q68DV7-1
ENSG00000285897	ENST00000648873.1 link	n.350G>A		non_coding_transcript_exon_variant	Exon 2 of 13			ENSP00000497686.1		A0A3B3ITA1

Frequencies

GnomAD3 genomes

AF:

0.148

AC:

22491

AN:

151854

Hom.:

1958

Cov.:

show subpopulations

Gnomad AFR

AF:

0.186

Gnomad AMI

AF:

0.146

Gnomad AMR

AF:

0.0981

Gnomad ASJ

AF:

0.156

Gnomad EAS

AF:

0.375

Gnomad SAS

AF:

0.313

Gnomad FIN

AF:

0.148

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.108

Gnomad OTH

AF:

0.128

GnomAD3 exomes

AF:

0.158

AC:

38482

AN:

243942

Hom.:

4107

AF XY:

0.164

AC XY:

21617

AN XY:

131756

show subpopulations

Gnomad AFR exome

AF:

0.189

Gnomad AMR exome

AF:

0.0710

Gnomad ASJ exome

AF:

0.165

Gnomad EAS exome

AF:

0.386

Gnomad SAS exome

AF:

0.291

Gnomad FIN exome

AF:

0.151

Gnomad NFE exome

AF:

0.109

Gnomad OTH exome

AF:

0.133

GnomAD4 exome

AF:

0.128

AC:

185550

AN:

1453312

Hom.:

14975

Cov.:

AF XY:

0.132

AC XY:

95544

AN XY:

722512

show subpopulations

Gnomad4 AFR exome

AF:

0.187

Gnomad4 AMR exome

AF:

0.0743

Gnomad4 ASJ exome

AF:

0.166

Gnomad4 EAS exome

AF:

0.354

Gnomad4 SAS exome

AF:

0.290

Gnomad4 FIN exome

AF:

0.146

Gnomad4 NFE exome

AF:

0.105

Gnomad4 OTH exome

AF:

0.143

GnomAD4 genome

AF:

0.148

AC:

22517

AN:

151972

Hom.:

1963

Cov.:

AF XY:

0.154

AC XY:

11419

AN XY:

74256

show subpopulations

Gnomad4 AFR

AF:

0.186

Gnomad4 AMR

AF:

0.0982

Gnomad4 ASJ

AF:

0.156

Gnomad4 EAS

AF:

0.374

Gnomad4 SAS

AF:

0.312

Gnomad4 FIN

AF:

0.148

Gnomad4 NFE

AF:

0.108

Gnomad4 OTH

AF:

0.132

Alfa

AF:

0.118

Hom.:

3334

Bravo

AF:

0.143

TwinsUK

AF:

0.110

AC:

408

ALSPAC

AF:

0.107

AC:

414

ESP6500AA

AF:

0.185

AC:

816

ESP6500EA

AF:

0.109

AC:

936

ExAC

AF:

0.160

AC:

19385

Asia WGS

AF:

0.341

AC:

1186

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 18, 2024

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

RNF43-related disorder

Benign:1

Nov 04, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.23

T;T;T

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.86

.;.;D

MetaRNN

Benign

0.0032

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.55

N;N;N

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-2.4

N;.;.

REVEL

Benign

0.14

Sift

Uncertain

0.0010

D;.;.

Sift4G

Uncertain

0.016

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.14

MPC

0.53

ClinPred

0.019

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.54

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over