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RNF43c.1403C>TUncertain significance
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Variant interpretation report

RNF43 c.1403C>T, p.(Ser468Leu)

NM_017763.5:c.1403C>T NP_060233.3:p.(Ser468Leu) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About RNF43

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV68458360, n = 2 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 1 met · 21 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

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).

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).

Met · 1

PM2 SupportingVariant is absent from gnomAD v2.1 and v4.1 population databases, consistent with PM2 at supporting level for a rare missense variant. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes/genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 21 · evaluated, threshold not reached

PS2 No de novo occurrence data available for this variant; no pedigree or parentage information in evidence sources. Details ▾Hide ▴
Still missing
  • No de novo testing or family studies available.
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. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional evidence curated.
Still missing
  • No functional assays performed on this variant.
Sources
oncokb ↗
PS4 No case-control or prevalence data available; variant is absent from population databases but no affected-vs-control comparison has been performed. Details ▾Hide ▴
Still missing
  • No case-control studies or cohort prevalence data available.
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. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: residue not significant.
  • No evidence of critical functional domain enrichment.
Still missing
  • No domain-level constraint data available for RNF43.
Sources
oncokb ↗
PM6 No assumed de novo evidence available; no reports of this variant occurring de novo in any publication or database. Details ▾Hide ▴
Still missing
  • No de novo reports for this variant.
PP1 No cosegregation data available; no family studies including this variant found. Details ▾Hide ▴
Still missing
  • No family segregation data available.
PP2 RNF43 disease mechanism is primarily loss-of-function; HCI prior data unavailable to assess missense constraint. Cannot establish that missense variants in RNF43 have a low rate of benign variation and are a common disease mechanism. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for RNF43.
  • Primary disease mechanism is LOF
  • not specifically missense.
Still missing
  • No gene-level missense constraint metric available.
Sources
pvs1_gene_context
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. Multiple computational tools do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.37 (equivocal
  • below 0.5 threshold).
  • BayesDel: -0.227 (not damaging).
  • SpliceAI: max delta 0.01 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or clinical data available to assess specificity of presentation for RNF43-related disease. Details ▾Hide ▴
Still missing
  • No clinical phenotype data provided for this case.
PP5 No reputable source has reported this variant as pathogenic; variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no submitter classifications available.
Sources
clinvar ↗
BA1 Variant is absent from gnomAD v2.1 and v4.1; allele frequency does not exceed BA1 threshold of >1% in any population. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Variant is absent from gnomAD; allele frequency does not exceed BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data on observation of this variant in healthy adults with full penetrance expected at an early age. Details ▾Hide ▴
Still missing
  • No data on healthy adult carriers.
BS3 No functional studies demonstrating no deleterious effect are available for this variant. Details ▾Hide ▴
Still missing
  • No functional studies performed on this variant.
BS4 No segregation data available to demonstrate lack of cosegregation with disease. Details ▾Hide ▴
Still missing
  • No family segregation data available.
BP1 RNF43 is associated with disease through loss-of-function but missense variants cannot be categorically excluded as a disease mechanism. The gene is not definitively established as truncating-only. Details ▾Hide ▴
Evidence considered
  • RNF43 LOF mechanism supported but missense variants are not excluded as pathogenic.
Sources
pvs1_gene_context
BP2 No data on observation of this variant in trans with a pathogenic variant in a recessive disorder. Details ▾Hide ▴
Still missing
  • No phase data available.
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. Multiple lines of computational evidence do not consistently predict no effect on the gene product. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.37 (indeterminate).
  • BayesDel: -0.227 (mildly benign).
  • SpliceAI: max delta 0.01 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP5 No evidence that this variant is found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No alternate molecular diagnosis data available.
BP6 No reputable source has reported this variant as benign; variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no benign classifications from any submitter.
Sources
clinvar ↗
PS5 No de novo evidence available to support this criterion. Details ▾Hide ▴
Still missing
  • No de novo reports for this variant.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Ser468Leu); does not fall into null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Variant is a missense substitution
  • not a predicted null variant.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ANo different pathogenic nucleotide change at c.1403 identified that produces the same amino acid change (p.Ser468Leu). Details ▾Hide ▴
Evidence considered
  • No alternative nucleotide changes at codon 468 identified in ClinVar.
Sources
clinvar ↗pm5_candidates
PM5 N/ANo same-residue pathogenic comparator variant identified in ClinVar at codon 468; automatic PM5 candidate harvesting produced no candidates. Details ▾Hide ▴
Evidence considered
  • No pathogenic or likely pathogenic variants at residue 468 found in ClinVar.
Sources
pm5_candidates
BP7 N/AThis is a missense variant (p.Ser468Leu), not a synonymous variant; BP7 applies only to silent variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Identifiers

Gene
RNF43
Transcript
NM_017763.5
Coding (HGVS c.)
NM_017763.5:c.1403C>T
Protein (HGVS p.)
NP_060233.3:p.(Ser468Leu)
GRCh38
chr17:58358373 G>A
GRCh37
chr17:56435734 G>A
COSMIC
COSV68458360

Gene diagram

Every interpreted variant in RNF43, mapped onto the exon structure of NM_017763.5. Select a row to find it on the plot.

RNF43NM_017763.5
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -55 bp
0.000
SpliceAI acceptor gainat +171 bp
0.000
SpliceAI donor lossat +31 bp
0.010
SpliceAI donor gainat +406 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
0.370
BayesDel
-0.227

How the predictions were used

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. Multiple computational tools do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.37 (equivocal
  • below 0.5 threshold).
  • BayesDel: -0.227 (not damaging).
  • SpliceAI: max delta 0.01 (no splice impact).
Sources
revelbayesdelspliceai ↗
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. Multiple lines of computational evidence do not consistently predict no effect on the gene product. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.37 (indeterminate).
  • BayesDel: -0.227 (mildly benign).
  • SpliceAI: max delta 0.01 (no splicing impact).
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (p.Ser468Leu), not a synonymous variant; BP7 applies only to silent variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Variant is missense
  • not synonymous.

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from 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.

Functional

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.

Somatic

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

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.