17-58354951-C-G

Position:

• chr17-58354951-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_017763.6(RNF43):​c.2344G>C​(p.Ala782Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: RNF43 NM_017763.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21532536).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF43	NM_017763.6	c.2344G>C	p.Ala782Pro	missense_variant	10/10	ENST00000407977.7	NP_060233.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF43	ENST00000407977.7	c.2344G>C	p.Ala782Pro	missense_variant	10/10	2	NM_017763.6	ENSP00000385328.2
ENSG00000285897	ENST00000648873.1	n.2308+2517G>C		intron_variant				ENSP00000497686.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 26, 2024

The p.A782P variant (also known as c.2344G>C), located in coding exon 9 of the RNF43 gene, results from a G to C substitution at nucleotide position 2344. The alanine at codon 782 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.033	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.048	T;.;T;T;.
Eigen	Uncertain	0.25
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.78	.;T;.;T;T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.22	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;N;N;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.9	N;.;.;.;.
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;.;.;.;.
Sift4G	Uncertain	0.018	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.48
MutPred		0.15		Gain of loop (P = 0.0502);.;Gain of loop (P = 0.0502);Gain of loop (P = 0.0502);.;
MVP		0.37
MPC		1.1
ClinPred		0.87	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.54

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: rs1390446946; hg19: chr17-56432312;