NM_017763.5:c.1403C>T

RNF43 · NP_060233.3:p.(Ser468Leu) · NM_017763.5

GRCh37: chr17:56435734 G>A · GRCh38: chr17:58358373 G>A

Gene: RNF43 Transcript: NM_017763.5

Final call

VUS

PM2 supporting

Variant details

Gene

RNF43

Transcript

NM_017763.5

Protein

NP_060233.3:p.(Ser468Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Missense 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).	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	No different pathogenic nucleotide change at c.1403 identified that produces the same amino acid change (p.Ser468Leu).	clinvar pm5_candidates
PS2	Not met	No de novo occurrence data available for this variant; no pedigree or parentage information in evidence sources.
PS3	Not met	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.	oncokb
PS4	Not met	No case-control or prevalence data available; variant is absent from population databases but no affected-vs-control comparison has been performed.
PS5	Not met	No de novo evidence available to support this criterion.
PM1	Not met	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.	oncokb
PM2	Met	Variant is absent from gnomAD v2.1 and v4.1 population databases, consistent with PM2 at supporting level for a rare missense variant.	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue pathogenic comparator variant identified in ClinVar at codon 468; automatic PM5 candidate harvesting produced no candidates.	pm5_candidates
PM6	Not met	No assumed de novo evidence available; no reports of this variant occurring de novo in any publication or database.
PP1	Not met	No cosegregation data available; no family studies including this variant found.
PP2	Not met	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.	pvs1_gene_context
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or clinical data available to assess specificity of presentation for RNF43-related disease.
PP5	Not met	No reputable source has reported this variant as pathogenic; variant is absent from ClinVar.	clinvar
BA1	Not met	Variant is absent from gnomAD v2.1 and v4.1; allele frequency does not exceed BA1 threshold of >1% in any population.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from gnomAD; allele frequency does not exceed BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No data on observation of this variant in healthy adults with full penetrance expected at an early age.
BS3	Not met	No functional studies demonstrating no deleterious effect are available for this variant.
BS4	Not met	No segregation data available to demonstrate lack of cosegregation with disease.
BP1	Not met	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.	pvs1_gene_context
BP2	Not met	No data on observation of this variant in trans with a pathogenic variant in a recessive disorder.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not met	No evidence that this variant is found in a case with an alternate molecular basis for disease.
BP6	Not met	No reputable source has reported this variant as benign; variant is absent from ClinVar.	clinvar
BP7	N/A	This is a missense variant (p.Ser468Leu), not a synonymous variant; BP7 applies only to silent variants with no predicted splice impact.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.