rs2526374

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L418I) has been classified as Uncertain significance.

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:8

Conservation

PhyloP100: 2.49

Publications

41 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 403384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017763.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RNF43	NM_017763.6	MANE Select	c.1252C>A	p.Leu418Met	missense	Exon 9 of 10	NP_060233.3
RNF43	NM_001438820.1		c.1252C>A	p.Leu418Met	missense	Exon 10 of 10	NP_001425749.1
RNF43	NM_001438821.1		c.1252C>A	p.Leu418Met	missense	Exon 9 of 9	NP_001425750.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RNF43	ENST00000407977.7	TSL:2 MANE Select	c.1252C>A	p.Leu418Met	missense	Exon 9 of 10	ENSP00000385328.2
RNF43	ENST00000577716.5	TSL:1	c.1252C>A	p.Leu418Met	missense	Exon 9 of 10	ENSP00000462764.1
RNF43	ENST00000584437.5	TSL:1	c.1252C>A	p.Leu418Met	missense	Exon 8 of 9	ENSP00000463069.1

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

GnomAD2 exomes

AF:

0.395

AC:

98463

AN:

249256

AF XY:

0.387

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 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

African (AFR)

AF:

0.414

AC:

13873

AN:

33478

American (AMR)

AF:

0.542

AC:

24161

AN:

44562

Ashkenazi Jewish (ASJ)

AF:

0.336

AC:

8768

AN:

26088

East Asian (EAS)

AF:

0.447

AC:

17740

AN:

39680

South Asian (SAS)

AF:

0.360

AC:

30984

AN:

86144

European-Finnish (FIN)

AF:

0.321

AC:

17087

AN:

53204

Middle Eastern (MID)

AF:

0.365

AC:

2102

AN:

5764

European-Non Finnish (NFE)

AF:

0.363

AC:

403259

AN:

1111580

Other (OTH)

AF:

0.371

AC:

22416

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

21613

43225

64838

86450

108063

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

12984

25968

38952

51936

64920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.378

AC:

57488

AN:

152088

Hom.:

10990

Cov.:

AF XY:

0.377

AC XY:

28006

AN XY:

74354

show subpopulations

African (AFR)

AF:

0.400

AC:

16571

AN:

41468

American (AMR)

AF:

0.437

AC:

6683

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.334

AC:

1157

AN:

3464

East Asian (EAS)

AF:

0.451

AC:

2330

AN:

5172

South Asian (SAS)

AF:

0.366

AC:

1770

AN:

4832

European-Finnish (FIN)

AF:

0.319

AC:

3378

AN:

10580

Middle Eastern (MID)

AF:

0.412

AC:

121

AN:

294

European-Non Finnish (NFE)

AF:

0.359

AC:

24385

AN:

67966

Other (OTH)

AF:

0.376

AC:

793

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1885

3770

5654

7539

9424

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

558

1116

1674

2232

2790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.371

Hom.:

46261

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

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

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jun 14, 2019

GeneDx

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

Hereditary cancer-predisposing syndrome

Benign:1

Jul 10, 2025

GeneKor MSA

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.054

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.27

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.73

MetaRNN

Benign

0.00019

MetaSVM

Benign

-0.92

MutationAssessor

Benign

1.9

PhyloP100

2.5

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.91

REVEL

Benign

0.11

Sift

Benign

0.064

Sift4G

Uncertain

0.050

Polyphen

0.95

Vest4

0.071

MPC

0.41

ClinPred

0.015

GERP RS

4.2

Varity_R

0.11

gMVP

0.11

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over