rs3744093

Variant names:

• chr17-58415439-T-C
• rs3744093
• NM_017763.6:c.139A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (9775 hom., cov: 33)
  • Exomes 𝑓: 0.39 (113478 hom.)
• Consequence: RNF43 NM_017763.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.12
• Publications: 57 publications found

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]

ENSG00000285897 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 403385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.496 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RNF43	NM_017763.6	c.139A>G	p.Ile47Val	missense_variant	Exon 2 of 10	ENST00000407977.7	NP_060233.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RNF43	ENST00000407977.7	c.139A>G	p.Ile47Val	missense_variant	Exon 2 of 10	2	NM_017763.6	ENSP00000385328.2
ENSG00000285897	ENST00000648873.1	n.139A>G		non_coding_transcript_exon_variant	Exon 1 of 13			ENSP00000497686.1

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52718 AN: 152078 Hom.: 9761 Cov.: 33

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

GnomAD2 exomes AF: 0.412 AC: 103689 AN: 251416 AF XY: 0.409

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 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.: 44 AF XY: 0.390 AC XY: 283480 AN XY: 727182

African (AFR) AF: 0.213 AC: 7139 AN: 33480

American (AMR) AF: 0.561 AC: 25104 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 10200 AN: 26136

East Asian (EAS) AF: 0.520 AC: 20631 AN: 39700

South Asian (SAS) AF: 0.412 AC: 35519 AN: 86254

European-Finnish (FIN) AF: 0.363 AC: 19355 AN: 53388

Middle Eastern (MID) AF: 0.334 AC: 1928 AN: 5768

European-Non Finnish (NFE) AF: 0.384 AC: 427221 AN: 1111890

Other (OTH) AF: 0.384 AC: 23165 AN: 60390

GnomAD4 genome AF: 0.347 AC: 52755 AN: 152196 Hom.: 9775 Cov.: 33 AF XY: 0.348 AC XY: 25896 AN XY: 74410

African (AFR) AF: 0.219 AC: 9097 AN: 41556

American (AMR) AF: 0.446 AC: 6819 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.384 AC: 1333 AN: 3472

East Asian (EAS) AF: 0.513 AC: 2651 AN: 5170

South Asian (SAS) AF: 0.406 AC: 1956 AN: 4812

European-Finnish (FIN) AF: 0.359 AC: 3803 AN: 10598

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25820 AN: 67990

Other (OTH) AF: 0.362 AC: 765 AN: 2112

Alfa AF: 0.372 Hom.: 26786

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

Submissions by phenotype

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

- -

not specified Benign:2

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. -

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 -

Hereditary cancer-predisposing syndrome Benign:1

Sep 12, 2023

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	17
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	D
LIST_S2	Benign	0.72	.;T;.;T
MetaRNN	Benign	0.00019	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.34	N;N;N;N
PhyloP100		1.1
PrimateAI	Benign	0.39	T
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	T
GERP RS		3.2
PromoterAI		-0.0080	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.071
gMVP		0.60
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3744093; hg19: chr17-56492800; COSMIC: COSV60415571; COSMIC: COSV60415571;