rs2526374

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.1252C>A(p.Leu418Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,612,932 control chromosomes in the GnomAD database, including 112,612 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict 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 0.38 ( 10990 hom., cov: 33)

Exomes 𝑓: 0.37 ( 101622 hom. )

Consequence

RNF43
NM_017763.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.49

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=1.885891E-4).

BP6

Variant 17-58358524-G-T is Benign according to our data. Variant chr17-58358524-G-T is described in ClinVar as [Benign]. Clinvar id is 403384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58358524-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.435 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF43	NM_017763.6 link	c.1252C>A	p.Leu418Met	missense_variant	Exon 9 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.1252C>A	p.Leu418Met	missense_variant	Exon 9 of 10	2	NM_017763.6	ENSP00000385328.2		Q68DV7-1
ENSG00000285897	ENST00000648873.1 link	n.1252C>A		non_coding_transcript_exon_variant	Exon 8 of 13			ENSP00000497686.1		A0A3B3ITA1

Frequencies

GnomAD3 genomes

AF:

0.378

AC:

57445

AN:

151970

Hom.:

10974

Cov.:

show subpopulations

Gnomad AFR

AF:

0.400

Gnomad AMI

AF:

0.331

Gnomad AMR

AF:

0.437

Gnomad ASJ

AF:

0.334

Gnomad EAS

AF:

0.451

Gnomad SAS

AF:

0.367

Gnomad FIN

AF:

0.319

Gnomad MID

AF:

0.399

Gnomad NFE

AF:

0.359

Gnomad OTH

AF:

0.375

GnomAD3 exomes

AF:

0.395

AC:

98463

AN:

249256

Hom.:

20261

AF XY:

0.387

AC XY:

52111

AN XY:

134728

show subpopulations

Gnomad AFR exome

AF:

0.405

Gnomad AMR exome

AF:

0.561

Gnomad ASJ exome

AF:

0.336

Gnomad EAS exome

AF:

0.460

Gnomad SAS exome

AF:

0.367

Gnomad FIN exome

AF:

0.317

Gnomad NFE exome

AF:

0.360

Gnomad OTH exome

AF:

0.384

GnomAD4 exome

AF:

0.370

AC:

540390

AN:

1460844

Hom.:

101622

Cov.:

AF XY:

0.368

AC XY:

267707

AN XY:

726646

show subpopulations

Gnomad4 AFR exome

AF:

0.414

Gnomad4 AMR exome

AF:

0.542

Gnomad4 ASJ exome

AF:

0.336

Gnomad4 EAS exome

AF:

0.447

Gnomad4 SAS exome

AF:

0.360

Gnomad4 FIN exome

AF:

0.321

Gnomad4 NFE exome

AF:

0.363

Gnomad4 OTH exome

AF:

0.371

GnomAD4 genome

AF:

0.378

AC:

57488

AN:

152088

Hom.:

10990

Cov.:

AF XY:

0.377

AC XY:

28006

AN XY:

74354

show subpopulations

Gnomad4 AFR

AF:

0.400

Gnomad4 AMR

AF:

0.437

Gnomad4 ASJ

AF:

0.334

Gnomad4 EAS

AF:

0.451

Gnomad4 SAS

AF:

0.366

Gnomad4 FIN

AF:

0.319

Gnomad4 NFE

AF:

0.359

Gnomad4 OTH

AF:

0.376

Alfa

AF:

0.369

Hom.:

25622

Bravo

AF:

0.391

TwinsUK

AF:

0.358

AC:

1329

ALSPAC

AF:

0.359

AC:

1383

ESP6500AA

AF:

0.402

AC:

1773

ESP6500EA

AF:

0.359

AC:

3088

ExAC

AF:

0.389

AC:

47235

Asia WGS

AF:

0.397

AC:

1378

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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

Jun 14, 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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.054

T;.;T;T;.;.

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.73

.;T;.;T;T;T

MetaRNN

Benign

0.00019

T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.9

L;.;L;L;.;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.91

N;.;.;.;.;.

REVEL

Benign

0.11

Sift

Benign

0.064

T;.;.;.;.;.

Sift4G

Uncertain

0.050

T;T;T;T;T;D

Polyphen

0.95

P;D;P;P;.;.

Vest4

0.071

MPC

0.41

ClinPred

0.015

GERP RS

4.2

Varity_R

0.11

gMVP

0.11

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