rs786205215

Variant names:

• chr17-58363582-G-A
• rs786205215
• NM_017763.6:c.394C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-58363582-G-A
• chr17-58363582-G-C
• chr17-58363582-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_017763.6(RNF43):​c.394C>T​(p.Arg132*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,459,328 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: RNF43 NM_017763.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 1.57
• Publications: 20 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: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-58363582-G-A is Pathogenic according to our data. Variant chr17-58363582-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 190226.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF43	NM_017763.6	MANE Select	c.394C>T	p.Arg132*	stop_gained	Exon 4 of 10	NP_060233.3
	RNF43	NM_001438820.1		c.394C>T	p.Arg132*	stop_gained	Exon 5 of 10	NP_001425749.1
	RNF43	NM_001438821.1		c.394C>T	p.Arg132*	stop_gained	Exon 4 of 9	NP_001425750.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RNF43	ENST00000407977.7	TSL:2 MANE Select	c.394C>T	p.Arg132*	stop_gained	Exon 4 of 10	ENSP00000385328.2
	RNF43	ENST00000577716.5	TSL:1	c.394C>T	p.Arg132*	stop_gained	Exon 4 of 10	ENSP00000462764.1
	RNF43	ENST00000584437.5	TSL:1	c.394C>T	p.Arg132*	stop_gained	Exon 3 of 9	ENSP00000463069.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1459328 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725554

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.00 AC: 0 AN: 86114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53230

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110192

Other (OTH) AF: 0.0000166 AC: 1 AN: 60254

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Colon serrated polyposis (1)
1	-	-	Sessile serrated polyposis cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		1.6
Vest4		0.96
GERP RS		2.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		3.7
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs786205215; hg19: chr17-56440943; COSMIC: COSV68457376;