rs3744093

Positions:

chr17-58415439-T-C

Variant summary

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

The NM_017763.6(RNF43):c.139A>G(p.Ile47Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 1,613,924 control chromosomes in the GnomAD database, including 123,253 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.35 ( 9775 hom., cov: 33)

Exomes 𝑓: 0.39 ( 113478 hom. )

Consequence

RNF43
NM_017763.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.12

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:

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=1.9103289E-4).

BP6

Variant 17-58415439-T-C is Benign according to our data. Variant chr17-58415439-T-C is described in ClinVar as [Benign]. Clinvar id is 403385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58415439-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF43	NM_017763.6 linkuse as main transcript	c.139A>G	p.Ile47Val	missense_variant	2/10	ENST00000407977.7	NP_060233.3	Q68DV7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF43	ENST00000407977.7 linkuse as main transcript	c.139A>G	p.Ile47Val	missense_variant	2/10	2	NM_017763.6	ENSP00000385328.2		Q68DV7-1
ENSG00000285897	ENST00000648873.1 linkuse as main transcript	n.139A>G		non_coding_transcript_exon_variant	1/13			ENSP00000497686.1		A0A3B3ITA1

Frequencies

GnomAD3 genomes

AF:

0.347

AC:

52718

AN:

152078

Hom.:

9761

Cov.:

show subpopulations

Gnomad AFR

AF:

0.219

Gnomad AMI

AF:

0.449

Gnomad AMR

AF:

0.446

Gnomad ASJ

AF:

0.384

Gnomad EAS

AF:

0.513

Gnomad SAS

AF:

0.406

Gnomad FIN

AF:

0.359

Gnomad MID

AF:

0.345

Gnomad NFE

AF:

0.380

Gnomad OTH

AF:

0.364

GnomAD3 exomes

AF:

0.412

AC:

103689

AN:

251416

Hom.:

22528

AF XY:

0.409

AC XY:

55579

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.218

Gnomad AMR exome

AF:

0.580

Gnomad ASJ exome

AF:

0.389

Gnomad EAS exome

AF:

0.517

Gnomad SAS exome

AF:

0.417

Gnomad FIN exome

AF:

0.359

Gnomad NFE exome

AF:

0.384

Gnomad OTH exome

AF:

0.404

GnomAD4 exome

AF:

0.390

AC:

570262

AN:

1461728

Hom.:

113478

Cov.:

AF XY:

0.390

AC XY:

283480

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.213

Gnomad4 AMR exome

AF:

0.561

Gnomad4 ASJ exome

AF:

0.390

Gnomad4 EAS exome

AF:

0.520

Gnomad4 SAS exome

AF:

0.412

Gnomad4 FIN exome

AF:

0.363

Gnomad4 NFE exome

AF:

0.384

Gnomad4 OTH exome

AF:

0.384

GnomAD4 genome

AF:

0.347

AC:

52755

AN:

152196

Hom.:

9775

Cov.:

AF XY:

0.348

AC XY:

25896

AN XY:

74410

show subpopulations

Gnomad4 AFR

AF:

0.219

Gnomad4 AMR

AF:

0.446

Gnomad4 ASJ

AF:

0.384

Gnomad4 EAS

AF:

0.513

Gnomad4 SAS

AF:

0.406

Gnomad4 FIN

AF:

0.359

Gnomad4 NFE

AF:

0.380

Gnomad4 OTH

AF:

0.362

Alfa

AF:

0.379

Hom.:

19039

Bravo

AF:

0.354

TwinsUK

AF:

0.378

AC:

1400

ALSPAC

AF:

0.395

AC:

1523

ESP6500AA

AF:

0.217

AC:

958

ESP6500EA

AF:

0.385

AC:

3312

ExAC

AF:

0.405

AC:

49125

Asia WGS

AF:

0.440

AC:

1531

AN:

3478

EpiCase

AF:

0.387

EpiControl

AF:

0.377

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 18, 2024	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. -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Sep 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.026

T;.;T;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.72

.;T;.;T

MetaRNN

Benign

0.00019

T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.44

N;.;.;.

REVEL

Benign

0.062

Sift

Benign

0.27

T;.;.;.

Sift4G

Benign

0.49

T;T;T;T

Polyphen

0.0010

B;B;B;B

Vest4

0.049

MPC

0.34

ClinPred

0.0051

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.071

gMVP

0.60

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