Classification rationale

PM2 VUS

RNF43 c.1403C>T

NM_017763.5:c.1403C>T (p.Ser468Leu) is a missense variant in RNF43 absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).¹ No additional pathogenic or benign criteria are met. The variant is absent from ClinVar, has not been reported in the literature, and in silico predictions are equivocal (REVEL 0.37, BayesDel -0.227, SpliceAI max delta 0.01).² Based on generic ACMG/AMP 2015 classification rules, PM2_Supporting alone is insufficient to classify this variant as Likely Pathogenic or Likely Benign. The variant is classified as a Variant of Uncertain Significance (VUS).³

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 clinvar ↗revelbayesdelspliceai ↗

3 generic_acmg_combination_rules

Gene diagram · NM_017763.5 · variants mapped to exon structure

RNF43 NM_017763.5

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 20 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Variant is absent from gnomAD v2.1 and v4.1 population databases, consistent with PM2 at supporting level for a rare missense variant.

Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes/genomes).

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 20 not met · 0 not assessed

Pathogenic

PS2 No de novo occurrence data available for this variant; no pedigree or parentage information in evidence sources.

PS3 No variant-specific functional studies identified; OncoKB reports Unknown Oncogenic Effect; no published functional data for NM_017763.5:c.1403C>T found in the literature.

PS4 No case-control or prevalence data available; variant is absent from population databases but no affected-vs-control comparison has been performed.

PM1 Not located in a statistically significant mutational hotspot; residue p.Ser468 is not in a known functional domain without benign variation based on available evidence.

PM6 No assumed de novo evidence available; no reports of this variant occurring de novo in any publication or database.

PP1 No cosegregation data available; no family studies including this variant found.

PP2 RNF43 disease mechanism is primarily loss-of-function; HCI prior data unavailable to assess missense constraint.

PP3 In silico evidence is equivocal: REVEL score 0.37 is below the standard deleterious threshold of 0.5; BayesDel score -0.227 is not supportive of pathogenicity; SpliceAI max delta 0.01 indicates no splicing impact.

PP4 No patient phenotype or clinical data available to assess specificity of presentation for RNF43-related disease.

PP5 No reputable source has reported this variant as pathogenic; variant is absent from ClinVar.

Benign

BA1 Variant is absent from gnomAD v2.1 and v4.1; allele frequency does not exceed BA1 threshold of >1% in any population.

BS1 Variant is absent from gnomAD; allele frequency does not exceed BS1 threshold of >0.3%.

BS2 No data on observation of this variant in healthy adults with full penetrance expected at an early age.

BS3 No functional studies demonstrating no deleterious effect are available for this variant.

BS4 No segregation data available to demonstrate lack of cosegregation with disease.

BP1 RNF43 is associated with disease through loss-of-function but missense variants cannot be categorically excluded as a disease mechanism.

BP2 No data on observation of this variant in trans with a pathogenic variant in a recessive disorder.

BP4 In silico evidence is equivocal: REVEL 0.37 is indeterminate, BayesDel -0.227 provides only mild benign prediction, and SpliceAI max delta 0.01 shows no splicing impact.

BP5 No evidence that this variant is found in a case with an alternate molecular basis for disease.

BP6 No reputable source has reported this variant as benign; variant is absent from ClinVar.

N/A · 4 PVS1 · PS1 · PM5 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.37. BayesDel score = -0.227309.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RNF43, a ubiquitin ligase, is mutated in various cancers including gastrointestinal and gynecological cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV68458360, n = 2 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Re-run this variant?