Variant classification summary

NM_017763.6:c.662G>A

RNF43 · NP_060233.3:p.(Arg221Gln) · NM_017763.6

GRCh37: chr17:56439930 C>T · GRCh38: chr17:58362569 C>T

Gene: RNF43 Transcript: NM_017763.6

Final call

VUS

Variant details

Gene

RNF43

Transcript

NM_017763.6

Protein

NP_060233.3:p.(Arg221Gln)

gnomAD AF

0.0024590490019592826 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

No pathogenic or benign criterion was met or applied; under the generic ACMG/AMP 2015 combination rules, that leaves the variant classified as Variant of Uncertain Significance.

Final determination: Generic ACMG/AMP 2015 combination rule (no RNF43 VCEP/CSPEC exists): no applied pathogenic, likely pathogenic, benign, or likely benign combination threshold is satisfied because zero criteria are met (all criteria not_assessed/not_applicable/not_met), therefore the variant is 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	Not applicable: p.(Arg221Gln) is a missense substitution, so the null-variant mechanisms PVS1 requires (e.g., nonsense-mediated decay) are not triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: insufficient evidence was available to determine whether the identical amino acid change is an established pathogenic substitution.
PS2	Not assessed	Not assessed: no proband or parental genotype data existed, so a confirmed de novo occurrence could not be evaluated.	PMID:25741868 generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional study of p.(Arg221Gln) was available to demonstrate a damaging effect on protein function.	oncokb PMID:25741868
PS4	Not assessed	Not assessed: no case-control study of this variant exists, and its gnomAD frequency (0.49% overall, 6.0% East Asian) resembles a common polymorphism rather than a rare disease allele.	clinvar gnomad_v2 gnomad_v4 PMID:25741868
PM1	Not assessed	Not assessed: insufficient evidence was available to determine whether p.(Arg221Gln) falls in a mutational hotspot or critical protein domain.
PM2	Not assessed	Not assessed: insufficient evidence was available to evaluate the variant's rarity in population databases.
PM3	Not assessed	Not assessed: no observation of this variant in trans with a pathogenic allele exists, and germline RNF43 disease is primarily autosomal dominant.	PMID:25741868 generic_acmg_combination_rules pvs1_gene_context clinvar gnomad_v2
PM4	N/A	Not applicable: p.(Arg221Gln) is a missense substitution with no change in protein length, so there is nothing for PM4 to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: insufficient evidence was available to identify another pathogenic substitution at the same amino acid position.
PM6	Not assessed	Not assessed: no proband or parental genotype data existed, so an assumed de novo occurrence could not be evaluated.	PMID:25741868 generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no affected relatives were tested, so co-segregation of this variant with disease could not be evaluated.	PMID:25741868 generic_acmg_combination_rules
PP2	Not assessed	Not assessed: insufficient evidence was available to evaluate whether missense is a common disease mechanism in RNF43.
PP3	Not assessed	Not assessed: insufficient evidence was available from in silico predictions to evaluate this criterion.
PP4	Not assessed	Not assessed: no proband phenotype or family history was available, so phenotype specificity could not be evaluated.	clinvar PMID:25741868
PP5	Not met	Not met: no ClinVar expert panel has classified this exact variant as Pathogenic or Likely pathogenic; all eight submissions are from clinical laboratories.	clinvar
BA1	Not assessed	Not assessed: insufficient evidence was available to evaluate the variant against the BA1 population-frequency threshold.
BS1	Not assessed	Not assessed: insufficient evidence was available to evaluate the variant against the BS1 population-frequency threshold.
BS2	Not assessed	Not assessed: insufficient evidence was available to evaluate the variant's occurrence in healthy individuals.
BS3	Not assessed	Not assessed: no functional study of p.(Arg221Gln) was available to demonstrate a lack of damaging effect.	oncokb PMID:25741868
BS4	Not assessed	Not assessed: no affected relatives were tested, so the variant could neither be shown to segregate nor fail to segregate.	PMID:25741868 generic_acmg_combination_rules
BP1	Not assessed	Not assessed: insufficient evidence was available to evaluate whether loss-of-function is the predominant disease mechanism for RNF43.
BP2	Not assessed	Not assessed: no cis or trans co-occurrence with a pathogenic RNF43 variant was observed, and the dominant disorder is not fully penetrant.	PMID:25741868 generic_acmg_combination_rules pvs1_gene_context clinvar
BP3	N/A	Not applicable: p.(Arg221Gln) is a missense substitution, not an in-frame insertion or deletion in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not assessed	Not assessed: insufficient evidence was available from in silico predictions to evaluate this criterion.
BP5	Not assessed	Not assessed: no proband-level data existed to evaluate whether an alternative genetic cause explains the presentation.	clinvar
BP6	Not met	Not met: no ClinVar expert panel has classified this exact variant as Benign or Likely benign; the eight laboratory submissions do not qualify.	clinvar
BP7	N/A	Not applicable: p.(Arg221Gln) is a missense substitution, not a synonymous variant, so BP7 does not apply.	generic_acmg_combination_rules

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