0%
RNF43c.1148T>CLikely benign
Print report
Variant interpretation report

RNF43 c.1148T>C, p.(Met383Thr)

NM_017763.5:c.1148T>C NP_060233.3:p.(Met383Thr) View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely benign classification under the recorded framework.

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: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_017763.5:c.1148T>C is extremely rare in population databases. In gnomAD v2.1 exomes, the allele frequency is 0.00121% (2/165,256 alleles, 0 homozygotes). In gnomAD v4.1, the allele frequency is 0.00065% (10/1,546,206 alleles). Absent from gnomAD-Canada. This is well below the 0.1% PM2 threshold for a rare variant absent from population controls.

Benign criteria applied · 2
BP1Supporting
BP1 · supporting

NM_017763.5:c.1148T>C is a missense variant in RNF43, a gene for which primarily truncating variants (frameshift, nonsense) are known to cause disease. RNF43 loss-of-function via truncating mutations is the established mechanism for serrated polyposis syndrome. BP1 applies to missense variants in genes where the primary disease mechanism is truncating/LoF.

BP4Supporting
BP4 · supporting

Multiple lines of computational evidence predict no impact on the gene product. REVEL score is 0.029 (strongly benign-leaning), BayesDel score is -0.829 (negative/benign), and SpliceAI predicts no splicing impact (max delta = 0.01). All three independent in silico predictors are concordant for a benign effect.

Recorded classification: Likely benign

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, BP1 supporting benign, BP4 supporting benign; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.

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
10 / 1,546,206 alleles

gnomAD v4.1: 10 / 1,546,206 alleles. Recorded AF 6.46744e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.21024e-05; MAF= 0.00121%, 2/165256 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 7.06314e-05; MAF= 0.00706%, 1/14158 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. ClinVar API review status: criteria provided, single submitter.

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.

29 criteria with recorded statuses: 3 met · 21 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_017763.5:c.1148T>C (p.Met383Thr) is a missense variant in RNF43, a gene in which primarily truncating variants cause serrated polyposis syndrome through loss of function.

This variant is extremely rare in population databases, with an allele frequency of 0.00121% in gnomAD v2.1 (2/165,256 alleles) and 0.00065% in gnomAD v4.1 (10/1,546,206 alleles), with no homozygotes observed.

Multiple lines of computational evidence predict a benign effect: REVEL score 0.029 (benign-leaning), BayesDel score -0.829 (negative), and SpliceAI predicts no splice alteration (max delta 0.01).

This variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (ClinVar Variation ID: 1938526).

No variant-specific functional studies, segregation data, de novo observations, or case-control data are available for this variant.

The variant does not localize to a statistically significant mutational hotspot or well-characterized functional domain; residue 383 lies outside the RNF43 RING finger domain (residues ~270-313).

Met · 3

PM2 SupportingNM_017763.5:c.1148T>C is extremely rare in population databases. In gnomAD v2.1 exomes, the allele frequency is 0.00121% (2/165,256 alleles, 0 homozygotes). In gnomAD v4.1, the allele frequency is 0.00065% (10/1,546,206 alleles). Absent from gnomAD-Canada. This is well below the 0.1% PM2 threshold for a rare variant absent from population controls. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF = 1.21e-05 (0.00121%)
  • 2/165
  • 256 alleles
  • 0 homozygotes.
  • gnomAD v4.1: AF = 6.47e-06 (0.00065%)
  • 10/1
  • 546
  • 206 alleles
  • gnomAD-Canada: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP1 SupportingNM_017763.5:c.1148T>C is a missense variant in RNF43, a gene for which primarily truncating variants (frameshift, nonsense) are known to cause disease. RNF43 loss-of-function via truncating mutations is the established mechanism for serrated polyposis syndrome. BP1 applies to missense variants in genes where the primary disease mechanism is truncating/LoF. Details ▾Hide ▴
Evidence considered
  • RNF43 disease mechanism is primarily loss-of-function via truncating variants
  • germline LoF is the established mechanism for serrated polyposis syndrome.
Sources
pvs1_gene_context
BP4 SupportingMultiple lines of computational evidence predict no impact on the gene product. REVEL score is 0.029 (strongly benign-leaning), BayesDel score is -0.829 (negative/benign), and SpliceAI predicts no splicing impact (max delta = 0.01). All three independent in silico predictors are concordant for a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.029 (benign-leaning
  • well below 0.5 threshold).
  • BayesDel: -0.829 (negative
  • benign-leaning).
  • SpliceAI: max delta = 0.01 (no predicted splicing alteration).
Sources
revelbayesdelspliceai ↗

Not met · 21 · evaluated, threshold not reached

PS1 No alternate nucleotide change at c.1148 resulting in the same p.Met383Thr amino acid substitution has been identified as a previously established pathogenic variant. PS1 requires a different nucleotide change producing the same missense that is known to be pathogenic. Details ▾Hide ▴
Evidence considered
  • Only one nucleotide change (c.1148T>C) is known to produce p.Met383Thr
  • no alternate pathogenic variant at this position producing the same amino acid change has been reported.
PS2 No de novo observation has been reported for NM_017763.5:c.1148T>C. PS2 requires confirmation of a de novo occurrence with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
  • No de novo report found in ClinVar
  • literature
  • or other sources.
PS3 No variant-specific functional data exists for NM_017763.5:c.1148T>C (p.Met383Thr). OncoKB reports unknown oncogenic effect with no curated functional evidence for this variant. Literature search returned no papers with functional characterization of this missense change. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no variant-specific functional evidence curated.
Still missing
  • No experimental functional data available for p.Met383Thr.
Sources
oncokb ↗
PS4 No case-control prevalence data comparing affected versus unaffected individuals is available for NM_017763.5:c.1148T>C. PS4 requires statistically significant enrichment in affected individuals. Details ▾Hide ▴
Evidence considered
  • No case-control or prevalence data available.
Still missing
  • No affected-case prevalence data available.
PM1 Residue 383 is not a statistically significant mutational hotspot per cancerhotspots.org, and position 383 lies outside characterized functional domains of RNF43. The RING finger domain is located at residues ~270-313; position 383 resides in a disordered C-terminal region without established critical functional annotation. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: residue not significant
  • exact variant not listed.
  • Position 383 is outside the RNF43 RING finger domain (residues ~270-313) and not in a well-characterized functional domain.
PM5 No comparator missense variants at amino acid residue 383 have been identified. PM5 requires a different pathogenic missense change at the same residue; automated candidate harvesting found no same-residue candidates in ClinVar. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned 0 candidates at residue 383
  • no pathogenic comparator missense variants identified.
Sources
pm5_candidates
PM6 No de novo report exists for NM_017763.5:c.1148T>C. PM6 requires a de novo observation without confirmation of paternity and maternity. Details ▾Hide ▴
Evidence considered
  • No de novo report found in ClinVar or literature.
PP1 No cosegregation data is available for NM_017763.5:c.1148T>C. PP1 requires cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
  • No segregation or family study data available.
Still missing
  • No family segregation data.
PP2 RNF43 is a tumor suppressor gene where truncating and loss-of-function variants are the primary disease mechanism for serrated polyposis syndrome. There is no evidence that missense variants represent a common mechanism of disease for RNF43, and the gene's missense constraint profile has not been established for PP2 application. Details ▾Hide ▴
Evidence considered
  • RNF43 disease mechanism is primarily loss-of-function via truncating variants
  • no evidence that missense is a common pathogenic mechanism.
Still missing
  • No gene-level missense constraint metric (Z-score) available in evidence brief.
PP3 Multiple lines of in silico computational evidence predict a benign effect. REVEL score is 0.029 (well below the 0.5 threshold for pathogenicity), BayesDel score is -0.829 (negative, benign-leaning), and SpliceAI predicts no significant splice impact (max delta score = 0.01). All computational predictors are concordant for a neutral/benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.029 (benign-leaning).
  • BayesDel: -0.829 (benign-leaning).
  • SpliceAI: max delta = 0.01 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
PP4 No patient phenotype or clinical data is available for this case. PP4 requires the patient's phenotype or family history to be highly specific for the disease associated with RNF43 (serrated polyposis syndrome). Details ▾Hide ▴
Evidence considered
  • No patient phenotype or clinical history provided.
Still missing
  • Patient phenotype data is not available for PP4 assessment.
PP5 No reputable source has reported NM_017763.5:c.1148T>C as pathogenic. ClinVar reports this variant as Uncertain significance from a single clinical laboratory, which does not satisfy PP5. Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance (1 submitter)
  • no reputable source reports this as pathogenic.
Sources
clinvar ↗
BA1 The allele frequency of NM_017763.5:c.1148T>C is 0.00121% in gnomAD v2.1, far below the 1% BA1 threshold for a common benign polymorphism. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF = 0.00121%
  • well below 1% BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The allele frequency of NM_017763.5:c.1148T>C is 0.00121% in gnomAD v2.1, well below the 0.3% BS1 threshold. This variant is not common enough in population databases to be considered benign on frequency alone. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF = 0.00121%
  • well below 0.3% BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No observation of NM_017763.5:c.1148T>C in a healthy adult individual without disease has been reported. BS2 requires documented observation in trans with a pathogenic variant or in a healthy adult with complete penetrance expected at an early age. Details ▾Hide ▴
Evidence considered
  • No reported observation in healthy adult controls without disease phenotype.
Still missing
  • No data on observation in healthy adults.
BS3 No well-established functional studies demonstrate that NM_017763.5:c.1148T>C has no deleterious effect. No variant-specific functional data exists. BS3 is not met in the absence of direct experimental evidence. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional studies available.
Still missing
  • No functional data available to assess BS3.
BS4 No segregation data is available for affected family members. BS4 requires lack of cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No segregation data.
BP2 No data regarding observation in trans with a pathogenic variant is available. BP2 requires observation in trans with a dominant pathogenic variant for a fully penetrant disorder. Details ▾Hide ▴
Evidence considered
  • No data regarding in trans observation.
Still missing
  • No phase data available.
BP5 No alternative molecular basis for disease has been identified in a case harboring NM_017763.5:c.1148T>C. BP5 requires observation in a case with an alternate molecular cause for the phenotype. Details ▾Hide ▴
Evidence considered
  • No case with alternate molecular basis reported.
Still missing
  • No data on cases with alternative molecular diagnoses.
BP6 No reputable source reports NM_017763.5:c.1148T>C as benign. ClinVar classification is Uncertain significance (1 clinical laboratory), which does not satisfy BP6. BP6 requires a reputable source to classify the variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance
  • not reported as benign by any reputable source.
Sources
clinvar ↗
PS5 No reputable source has reported NM_017763.5:c.1148T>C as pathogenic. ClinVar classification is Uncertain significance from a single clinical laboratory. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Uncertain significance (1 clinical laboratory
  • criteria provided
  • single submitter).
Sources
clinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_017763.5:c.1148T>C is a missense variant (p.Met383Thr) and does not fall into the default PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
  • Missense variant (p.Met383Thr)
  • PVS1 applies only to null variants per ClinGen SVI PVS1 recommendations (PMC6185798).
PM3 N/APM3 applies only to recessive disorders. RNF43-associated disease (serrated polyposis syndrome) follows autosomal dominant inheritance; this criterion is not applicable. Details ▾Hide ▴

No further detail was recorded.

PM4 N/AThis is a missense substitution, not a protein-length altering variant (in-frame deletion/insertion, stop-loss, or initiation codon change). PM4 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP3 N/AThis is a substitution variant, not an in-frame deletion/insertion. BP3 applies only to in-frame indels in repetitive regions. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ANM_017763.5:c.1148T>C is a missense variant (p.Met383Thr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is specific to synonymous variants.

Identifiers

Gene
RNF43
Transcript
NM_017763.5
Coding (HGVS c.)
NM_017763.5:c.1148T>C
Protein (HGVS p.)
NP_060233.3:p.(Met383Thr)
GRCh38
chr17:58358628 A>G
GRCh37
chr17:56435989 A>G
ClinVar
1938526

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 10 / 1,546,206 alleles AF 6.47e-06 · 0 homozygotes · FAF 3.95e-05
gnomAD v2.1 2 / 165,256 alleles AF 1.21e-05 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.5e-06 · 10 / 1,546,206 alleles · 0 hom · FAF 3.9e-05
South Asian7 / 81,800 8.6e-05
East Asian2 / 43,070 4.6e-05
European (non-Finnish)1 / 1,144,326 8.7e-07
0 alternate alleles recorded in 7 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 1.2e-05 · 2 / 165,256 alleles · 0 hom
East Asian1 / 14,158 7.1e-05
South Asian1 / 19,766 5.1e-05
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.46744e-06; MAF= 0.00065%, 10/1546206 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 8.55746e-05; MAF= 0.00856%, 7/81800 alleles, homozygotes = 0); grpmax FAF= 3.948e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.21024e-05; MAF= 0.00121%, 2/165256 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 7.06314e-05; MAF= 0.00706%, 1/14158 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +23 bp
0.000
SpliceAI acceptor gainat -310 bp
0.000
SpliceAI donor lossat +156 bp
0.000
SpliceAI donor gainat +76 bp
0.010
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.020

Other predictors

REVEL
0.029
BayesDel
-0.828

How the predictions were used

BP4 SupportingMultiple lines of computational evidence predict no impact on the gene product. REVEL score is 0.029 (strongly benign-leaning), BayesDel score is -0.829 (negative/benign), and SpliceAI predicts no splicing impact (max delta = 0.01). All three independent in silico predictors are concordant for a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.029 (benign-leaning
  • well below 0.5 threshold).
  • BayesDel: -0.829 (negative
  • benign-leaning).
  • SpliceAI: max delta = 0.01 (no predicted splicing alteration).
Sources
revelbayesdelspliceai ↗
PP3 Multiple lines of in silico computational evidence predict a benign effect. REVEL score is 0.029 (well below the 0.5 threshold for pathogenicity), BayesDel score is -0.829 (negative, benign-leaning), and SpliceAI predicts no significant splice impact (max delta score = 0.01). All computational predictors are concordant for a neutral/benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.029 (benign-leaning).
  • BayesDel: -0.829 (benign-leaning).
  • SpliceAI: max delta = 0.01 (no predicted splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ANM_017763.5:c.1148T>C is a missense variant (p.Met383Thr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is specific to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.029. BayesDel score = -0.828496.

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 10 / 1,546,206 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= 6.46744e-06; MAF= 0.00065%, 10/1546206 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 8.55746e-05; MAF= 0.00856%, 7/81800 alleles, homozygotes = 0); grpmax FAF= 3.948e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 1.21024e-05; MAF= 0.00121%, 2/165256 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 7.06314e-05; MAF= 0.00706%, 1/14158 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 = 1938526)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.029. BayesDel score = -0.828496.

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.