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RNF43c.1196C>TUncertain significance
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Variant interpretation report

RNF43 c.1196C>T, p.(Pro399Leu)

NM_017763.5:c.1196C>T NP_060233.3:p.(Pro399Leu) 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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_017763.5:c.1196C>T is absent from population databases: gnomAD v2.1 (0/223,892 alleles), gnomAD v4.1 (0/1,595,338 alleles), and gnomAD-Canada v1.0. The observed allele frequency of 0.0% is well below the 0.1% PM2 threshold for rare variants.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple in silico tools consistently predict a benign effect: REVEL score 0.022 (strongly benign-leaning, well below pathogenic threshold), BayesDel score -0.736863 (benign-leaning), and SpliceAI max delta 0.01 (no predicted splicing impact). The convergent benign prediction from independent algorithms supports BP4 at supporting benign strength.

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, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, 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.

gnomAD v4.1
gnomAD v2.1
Population frequency
0 / 1,595,338 alleles

gnomAD v4.1: 0 / 1,595,338 alleles. Recorded AF 0. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/223892 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/15068 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.010 maximum delta

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

Applied · BP4 → SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance.

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
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

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: 2 met · 16 not met · 2 not assessed · 6 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.1196C>T (p.Pro399Leu) is absent from gnomAD v2.1 (0/223,892 alleles) and v4.1 (0/1,595,338 alleles), meeting PM2 at supporting strength.

Multiple in silico tools predict a benign effect: REVEL score 0.022, BayesDel score -0.736863, and SpliceAI max delta 0.01 with no predicted splice impact, meeting BP4 at supporting benign strength.

The variant is reported in ClinVar as Uncertain Significance by a single clinical testing laboratory (VariationID 2093022) with review status 'criteria provided, single submitter.' This does not satisfy PP5 or BP6 thresholds.

The variant is a missense substitution outside known null-variant buckets, so PVS1 is not applicable. No functional studies, segregation data, de novo observations, case-control evidence, or same-residue pathogenic comparators are available for this variant.

Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are present. These are at equal weight and do not meet any pathogenic, likely pathogenic, benign, or likely benign combination threshold.

Final classification: Uncertain Significance.

Met · 2

PM2 SupportingNM_017763.5:c.1196C>T is absent from population databases: gnomAD v2.1 (0/223,892 alleles), gnomAD v4.1 (0/1,595,338 alleles), and gnomAD-Canada v1.0. The observed allele frequency of 0.0% is well below the 0.1% PM2 threshold for rare variants. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 0/223
  • 892 alleles (AF=0.0%)
  • gnomAD v4.1: 0/1
  • 595
  • 338 alleles (AF=0.0%)
  • gnomAD-Canada v1.0: absent
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple in silico tools consistently predict a benign effect: REVEL score 0.022 (strongly benign-leaning, well below pathogenic threshold), BayesDel score -0.736863 (benign-leaning), and SpliceAI max delta 0.01 (no predicted splicing impact). The convergent benign prediction from independent algorithms supports BP4 at supporting benign strength. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.022 (benign-leaning
  • typical pathogenic threshold ~0.5)
  • BayesDel: -0.736863 (benign-leaning)
  • SpliceAI: max delta 0.01 (no predicted splice impact)
Sources
revelbayesdelspliceai ↗

Not met · 16 · evaluated, threshold not reached

PS2 No de novo observation of NM_017763.5:c.1196C>T has been reported in the available literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
  • No de novo evidence found in ClinVar submissions or literature
Still missing
  • No de novo data available for this variant
PS4 No case-control or statistical evidence demonstrates enrichment of NM_017763.5:c.1196C>T in affected individuals compared to controls. Details ▾Hide ▴
Evidence considered
  • No case-control studies or statistical enrichment data available
Still missing
  • No case-control data for this variant
PM1 The variant does not lie in a statistically significant mutational hotspot as determined by cancerhotspots.org, and no known functional domain with established pathogenic missense constraint has been demonstrated to include residue Pro399. Details ▾Hide ▴
Evidence considered
  • Hotspot analysis: residue not significant
  • variant not in any statistically enriched hotspot
Still missing
  • No functional domain-level missense constraint data for RNF43 residue 399
PP1 No segregation data are available for NM_017763.5:c.1196C>T; no co-segregation with disease in affected family members has been reported. Details ▾Hide ▴
Evidence considered
  • No segregation data identified in ClinVar or literature
Still missing
  • No family segregation studies available
PP2 RNF43 is not established as a gene where missense variants are the predominant pathogenic mechanism with a low rate of benign missense variation. Pathogenic RNF43 variants include both truncating and missense alterations across multiple disease contexts. Details ▾Hide ▴
Evidence considered
  • RNF43 pathogenic spectrum includes truncating variants
  • not a gene where only missense variants cause disease
Still missing
  • No gene-specific missense constraint metrics available
PP3 Multiple in silico tools predict a benign effect: REVEL score 0.022 (strongly benign-leaning, well below typical pathogenic threshold of ~0.5), BayesDel score -0.736863 (benign-leaning), and SpliceAI max delta 0.01 (no predicted splice impact). No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.022 (benign-leaning)
  • BayesDel: -0.736863 (benign-leaning)
  • SpliceAI: max delta 0.01 (no splice impact predicted)
Sources
revelbayesdelspliceai ↗
PP4 No phenotype specificity data are available; the variant has not been reported in a cohort where its presence is highly specific to a defined clinical presentation. Details ▾Hide ▴
Evidence considered
  • No phenotype specificity data available
Still missing
  • No phenotype data or cohort studies available for this variant
PP5 ClinVar reports this variant as Uncertain Significance (VariationID 2093022) from a single clinical testing laboratory (Labcorp Genetics/Invitae) with review status 'criteria provided, single submitter.' This does not constitute a reputable source reporting the variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 2093022: Uncertain significance
  • single submitter
  • criteria provided
Sources
clinvar ↗
BA1 NM_017763.5:c.1196C>T is absent from gnomAD (AF=0.0% in both v2.1 and v4.1), far below the 1% BA1 threshold for a benign stand-alone classification. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF: 0.0%
  • gnomAD v4.1 AF: 0.0%
  • Both far below BA1 threshold of >1%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 NM_017763.5:c.1196C>T is absent from gnomAD (AF=0.0% in both v2.1 and v4.1), far below the 0.3% BS1 threshold for a strong benign criterion. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF: 0.0%
  • gnomAD v4.1 AF: 0.0%
  • Both far below BS1 threshold of >0.3%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data are available regarding observation of this variant in homozygous state or in healthy adult controls. The variant is absent from gnomAD and no family studies are available. Details ▾Hide ▴
Evidence considered
  • No homozygous observations or unaffected control data available
Still missing
  • No homozygote or control cohort data
BS4 No segregation data in unaffected family members are available for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation data available
Still missing
  • No segregation data in unaffected relatives
BP1 RNF43 is not a gene where only truncating variants cause disease. Reported pathogenic variants in RNF43 include both missense and truncating alterations across serrated polyposis syndrome and other phenotypes. This missense variant does not qualify for BP1. Details ▾Hide ▴
Evidence considered
  • RNF43 has pathogenic missense variants in addition to truncating variants
  • Gene does not meet BP1 requirement of being a gene where only truncating variants cause disease
Sources
pvs1_gene_context
BP2 No evidence that NM_017763.5:c.1196C>T has been observed in trans with a known pathogenic variant in RNF43. Details ▾Hide ▴
Evidence considered
  • No trans-phase observations with pathogenic variants
Still missing
  • No phase data available
BP5 No alternative molecular basis for disease has been identified in a case where this variant was observed. Details ▾Hide ▴
Evidence considered
  • No alternative molecular diagnosis data available
Still missing
  • No alternative molecular basis data
BP6 ClinVar reports NM_017763.5:c.1196C>T as Uncertain Significance (VariationID 2093022) from a single submitter. The classification is not benign or likely benign from a reputable source, which is required for BP6. Details ▾Hide ▴
Evidence considered
  • ClinVar VariationID 2093022: Uncertain significance
  • not benign/likely benign
Sources
clinvar ↗

Not assessed · 2 · no assessment recorded

PS3 No variant-specific functional studies for NM_017763.5:c.1196C>T (p.Pro399Leu) were identified in the literature or OncoKB. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no curated functional evidence. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional evidence
Still missing
  • No functional studies available for this specific variant
Sources
oncokb ↗
BS3 No variant-specific functional studies demonstrating no deleterious effect for NM_017763.5:c.1196C>T (p.Pro399Leu) have been identified. OncoKB reports no curated functional evidence for this alteration. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no functional studies demonstrating no impact
Still missing
  • No benign functional studies available for this variant
Sources
oncokb ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_017763.5:c.1196C>T is a missense variant (p.Pro399Leu) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for generic PVS1 activation per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Variant is missense (Pro399Leu)
  • classified as 'other' bucket by PVS1 variant assessment scaffold
  • apply_generic_pvs1_framework = false per pvs1_variant_assessment.json
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/ANo pathogenic missense variant at the same amino acid residue (Pro399) with an established pathogenic mechanism has been identified; PM5 candidate harvesting confirmed no same-residue comparator is available. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search found no same-residue variants at Pro399
Sources
pm5_candidates
PM5 N/ANo pathogenic missense variant at the same amino acid residue (Pro399) with a different amino acid change was identified; PM5 candidate search returned zero same-residue comparators. Details ▾Hide ▴
Evidence considered
  • PM5 candidate harvesting found no same-residue comparators at Pro399
Sources
pm5_candidates
PM6 N/ARequires a de novo observation without confirmed maternity/paternity; no de novo reports exist for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo observations identified
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact. NM_017763.5:c.1196C>T is a missense variant (p.Pro399Leu), not synonymous. Details ▾Hide ▴
Evidence considered
  • Variant is missense (Pro399Leu)
  • not synonymous
  • BP7 not applicable
PS5 N/ARequires two independent de novo observations with confirmed maternity/paternity; no de novo reports exist for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo observations identified

Identifiers

Gene
RNF43
Transcript
NM_017763.5
Coding (HGVS c.)
NM_017763.5:c.1196C>T
Protein (HGVS p.)
NP_060233.3:p.(Pro399Leu)
GRCh38
chr17:58358580 G>A
GRCh37
chr17:56435941 G>A
ClinVar
2093022

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 0 / 1,595,338 alleles AF 0 · 0 homozygotes
gnomAD v2.1 0 / 223,892 alleles AF 0 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0 · 0 / 1,595,338 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

gnomAD v2.1

AF 0 · 0 / 223,892 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1595338 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74772 alleles, homozygotes = 0).

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/223892 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/15068 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -262 bp
0.000
SpliceAI acceptor gainat +2 bp
0.000
SpliceAI donor lossat +124 bp
0.010
SpliceAI donor gainat +19 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.020

Other predictors

REVEL
0.022
BayesDel
-0.737

How the predictions were used

BP4 SupportingMultiple in silico tools consistently predict a benign effect: REVEL score 0.022 (strongly benign-leaning, well below pathogenic threshold), BayesDel score -0.736863 (benign-leaning), and SpliceAI max delta 0.01 (no predicted splicing impact). The convergent benign prediction from independent algorithms supports BP4 at supporting benign strength. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.022 (benign-leaning
  • typical pathogenic threshold ~0.5)
  • BayesDel: -0.736863 (benign-leaning)
  • SpliceAI: max delta 0.01 (no predicted splice impact)
Sources
revelbayesdelspliceai ↗
PP3 Multiple in silico tools predict a benign effect: REVEL score 0.022 (strongly benign-leaning, well below typical pathogenic threshold of ~0.5), BayesDel score -0.736863 (benign-leaning), and SpliceAI max delta 0.01 (no predicted splice impact). No computational evidence supports pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.022 (benign-leaning)
  • BayesDel: -0.736863 (benign-leaning)
  • SpliceAI: max delta 0.01 (no splice impact predicted)
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact. NM_017763.5:c.1196C>T is a missense variant (p.Pro399Leu), not synonymous. Details ▾Hide ▴
Evidence considered
  • Variant is missense (Pro399Leu)
  • not synonymous
  • BP7 not applicable

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.022. BayesDel score = -0.736863.

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 0 / 1,595,338 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar 1 Uncertain significance 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

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1595338 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74772 alleles, homozygotes = 0).

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/223892 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/15068 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2093022)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.022. BayesDel score = -0.736863.

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 not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.