17-58355001-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_017763.6(RNF43):c.2309-15G>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.168 in 1,609,502 control chromosomes in the GnomAD database, including 23,599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2215 hom., cov: 32)
  • Exomes 𝑓: 0.17 (21384 hom.)
• Consequence: RNF43 NM_017763.6 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.771

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]

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

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 17-58355001-C-G is Benign according to our data. Variant chr17-58355001-C-G is described in ClinVar as [Benign]. Clinvar id is 403383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-58355001-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.189 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RNF43	NM_017763.6	c.2309-15G>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000407977.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RNF43	ENST00000407977.7	c.2309-15G>C		splice_polypyrimidine_tract_variant, intron_variant		2	NM_017763.6	P1
TSPOAP1-AS1	ENST00000583841.1	n.434+17322C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25723 AN: 151898 Hom.: 2207 Cov.: 32

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.189

Gnomad ASJ AF: 0.0775

Gnomad EAS AF: 0.198

Gnomad SAS AF: 0.115

Gnomad FIN AF: 0.216

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.173

Gnomad OTH AF: 0.160

GnomAD3 exomes AF: 0.163 AC: 40716 AN: 249950 Hom.: 3465 AF XY: 0.159 AC XY: 21446 AN XY: 135178

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.0812

Gnomad EAS exome AF: 0.193

Gnomad SAS exome AF: 0.120

Gnomad FIN exome AF: 0.212

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.146

GnomAD4 exome AF: 0.168 AC: 244159 AN: 1457486 Hom.: 21384 Cov.: 31 AF XY: 0.165 AC XY: 120011 AN XY: 725172

Gnomad4 AFR exome AF: 0.150

Gnomad4 AMR exome AF: 0.171

Gnomad4 ASJ exome AF: 0.0816

Gnomad4 EAS exome AF: 0.215

Gnomad4 SAS exome AF: 0.121

Gnomad4 FIN exome AF: 0.209

Gnomad4 NFE exome AF: 0.171

Gnomad4 OTH exome AF: 0.153

GnomAD4 genome AF: 0.169 AC: 25764 AN: 152016 Hom.: 2215 Cov.: 32 AF XY: 0.171 AC XY: 12704 AN XY: 74286

Gnomad4 AFR AF: 0.155

Gnomad4 AMR AF: 0.189

Gnomad4 ASJ AF: 0.0775

Gnomad4 EAS AF: 0.199

Gnomad4 SAS AF: 0.116

Gnomad4 FIN AF: 0.216

Gnomad4 NFE AF: 0.173

Gnomad4 OTH AF: 0.157

Alfa AF: 0.104 Hom.: 221

Bravo AF: 0.164

Asia WGS AF: 0.152 AC: 529 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
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, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	12
Dann	Benign	0.72

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

Other links and lift over

dbSNP: rs2158460; hg19: chr17-56432362; COSMIC: COSV56642823; COSMIC: COSV56642823;