Variant classification summary

NM_001903.5:c.1193A>G

CTNNA1 · NP_001894.2:p.(Asn398Ser) · NM_001903.5

GRCh37: chr5:138223228 A>G · GRCh38: chr5:138887539 A>G

Gene: CTNNA1 Transcript: NM_001903.5

Final call

VUS

BP4 supporting

Variant details

Gene

CTNNA1

Transcript

NM_001903.5

Protein

NP_001894.2:p.(Asn398Ser)

gnomAD AF

0.00013216629871072707 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 supporting: REVEL 0.079 meets the missense BP4 threshold of <=0.29.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting benign criterion does not meet the Benign or Likely Benign thresholds, so the final call is VUS.

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	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_001903.5:c.1193A>G in CTNNA1 is a missense substitution predicted to produce NP_001894.2:p.(Asn398Ser). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	PS1 could not be assessed because its agent did not produce valid output.
PS2	Not assessed	Not assessed: parental genotypes and confirmed maternity/paternity are not documented for a de novo CTNNA1 c.1193A>G observation.
PS3	Not assessed	Not assessed: no variant-specific validated functional assay or assay-control result for CTNNA1 p.Asn398Ser was identified.	clinvar PMID:27153395 PMID:32051609
PS4	Not assessed	Not assessed: no exact-variant case-control enrichment, odds ratio, or adequately documented affected-case series was identified.	generic_acmg_combination_rules PMID:27153395 PMID:32051609
PM1	Not assessed	PM1 could not be assessed because its agent did not produce valid output.
PM2	Not met	Not met: default all-comers AF is 0.000132166 in gnomAD v4.1, exceeding the 0.0001 PM2 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no affected-proband observation with a pathogenic variant and no phase information establishing trans or cis is reported.	clinvar generic_acmg_combination_rules
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_001903.5:c.1193A>G in CTNNA1 is a missense substitution predicted to produce NP_001894.2:p.(Asn398Ser). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	PM5 could not be assessed because its agent did not produce valid output.
PM6	Not assessed	Not assessed: no variant-specific assumed de novo occurrence or family-history context is documented for CTNNA1 c.1193A>G.
PP1	Not assessed	Not assessed: no informative affected or unaffected relatives, meioses, or phenotype-concordant segregation data are reported for CTNNA1 c.1193A>G.
PP2	Not assessed	PP2 could not be assessed because its agent did not produce valid output.
PP3	Not met	Not met: missense REVEL score 0.079 is below the PP3 supporting threshold of 0.644.	revel
PP4	Not assessed	Not assessed: no carrier phenotype or highly specific clinical diagnostic finding was supplied for this exact variant.	generic_acmg_combination_rules
PP5	Not met	Not met: ClinVar has 0 expert-panel submissions for the exact variant, and available laboratory assertions are not qualifying Pathogenic/Likely pathogenic expert-panel evidence.	clinvar
BA1	Not met	Not met: the highest gnomAD v4.1 subgroup frequency is 0.000467065, far below the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the highest gnomAD v4.1 subgroup frequency is 0.000467065, below the generic 0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v2.1 and v4.1 report zero homozygotes, so the BS2 healthy-homozygote observation is absent.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not assessed	Not assessed: no validated normal-function assay with appropriate controls for CTNNA1 p.Asn398Ser was identified.	clinvar PMID:27153395 PMID:32051609
BS4	Not assessed	Not assessed: no adequately tested affected relatives lacking CTNNA1 c.1193A>G are documented for non-segregation.
BP1	Not assessed	BP1 could not be assessed because its agent did not produce valid output.
BP2	Not assessed	Not assessed: no second pathogenic variant or cis/trans phase information is documented for this missense variant.	clinvar generic_acmg_combination_rules
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_001903.5:c.1193A>G in CTNNA1 is a missense substitution predicted to produce NP_001894.2:p.(Asn398Ser). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting strength: missense REVEL score 0.079 meets the BP4 threshold of <=0.29.	revel
BP5	Not assessed	Not assessed: no affected case with a documented alternate molecular explanation was supplied for this exact variant.	generic_acmg_combination_rules clinvar
BP6	Not met	Not met: ClinVar has 0 expert-panel submissions; the exact-variant Benign and Likely benign assertions are single-submitter laboratory records.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_001903.5:c.1193A>G in CTNNA1 is a missense substitution predicted to produce NP_001894.2:p.(Asn398Ser). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules

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