NM_017763.5:c.1148T>C

RNF43 · NP_060233.3:p.(Met383Thr) · NM_017763.5

GRCh37: chr17:56435989 A>G · GRCh38: chr17:58358628 A>G

Gene: RNF43 Transcript: NM_017763.5

Final call

Likely Benign

PM2 supporting BP1 supporting benign BP4 supporting benign

Variant details

Gene

RNF43

Transcript

NM_017763.5

Protein

NP_060233.3:p.(Met383Thr)

gnomAD AF

6.467443535984209e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.
PS1	Not met	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.
PS2	Not met	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.
PS3	Not met	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.	oncokb
PS4	Not met	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.
PS5	Not met	No reputable source has reported NM_017763.5:c.1148T>C as pathogenic. ClinVar classification is Uncertain significance from a single clinical laboratory.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	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.	pm5_candidates
PM6	Not met	No de novo report exists for NM_017763.5:c.1148T>C. PM6 requires a de novo observation without confirmation of paternity and maternity.
PP1	Not met	No cosegregation data is available for NM_017763.5:c.1148T>C. PP1 requires cosegregation with disease in multiple affected family members.
PP2	Not met	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	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).
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	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.
BS3	Not met	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.
BS4	Not met	No segregation data is available for affected family members. BS4 requires lack of cosegregation with disease in multiple affected family members.
BP1	Met	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.	pvs1_gene_context
BP2	Not met	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.
BP4	Met	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.	revel bayesdel spliceai
BP5	Not met	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.
BP6	Not met	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.	clinvar
BP7	N/A	NM_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.
BP3	N/A	This is a substitution variant, not an in-frame deletion/insertion. BP3 applies only to in-frame indels in repetitive regions.
PM3	N/A	PM3 applies only to recessive disorders. RNF43-associated disease (serrated polyposis syndrome) follows autosomal dominant inheritance; this criterion is not applicable.
PM4	N/A	This is a missense substitution, not a protein-length altering variant (in-frame deletion/insertion, stop-loss, or initiation codon change). PM4 is not applicable.

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