Variant classification summary

NM_001903.5:c.710A>G

CTNNA1 · NP_001894.2:p.(Tyr237Cys) · NM_001903.5

GRCh37: chr5:138160340 A>G · GRCh38: chr5:138824651 A>G

Gene: CTNNA1 Transcript: NM_001903.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

CTNNA1

Transcript

NM_001903.5

Protein

NP_001894.2:p.(Tyr237Cys)

gnomAD AF

4.832360459396401e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 allele frequency is below the generic supporting threshold.

2

BP4 supporting: REVEL 0.278 meets the generic supporting benign threshold.

3

VUS: PM2 supporting plus BP4 supporting does not meet a generic ACMG/AMP classification threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting pathogenic criterion plus one supporting benign criterion does not satisfy any pathogenic, likely pathogenic, benign, or likely benign combination, so the 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.710A>G in CTNNA1 is a missense substitution predicted to produce NP_001894.2:p.(Tyr237Cys). 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	Not assessed: no established pathogenic variant with the same Tyr237Cys amino-acid change was identified in the available evidence.	clinvar PMID:25741868
PS2	Not assessed	Not assessed: no confirmed de novo occurrence or parental genotypes are documented for CTNNA1 c.710A>G.
PS3	Not assessed	Not assessed: no validated variant-specific functional assay or abnormal experimental result was available for CTNNA1 p.Tyr237Cys.
PS4	Not assessed	Not assessed: no variant-specific case-control enrichment, prevalence comparison, or affected-case series was identified for CTNNA1 c.710A>G.	clinvar PMID:25394175 PMID:34043773 PMID:35957908 PMID:34326862
PM1	Not met	Not met: residue Tyr237 is not in a documented critical domain or statistically significant hotspot, and no gene-specific domain table applies.	PMID:25741868
PM2	Met	Met at supporting strength: gnomAD v4.1 AF 4.83236e-05 is below the supplied PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband observation, pathogenic variant in trans, or phase evidence is documented for this CTNNA1 variant.	clinvar PMID:25741868
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.710A>G in CTNNA1 is a missense substitution predicted to produce NP_001894.2:p.(Tyr237Cys). 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	Not assessed: no pathogenic or likely pathogenic alternate missense variant at CTNNA1 residue 237 was identified for comparison.	clinvar PMID:25741868
PM6	Not assessed	Not assessed: no presumed de novo occurrence with incomplete parental testing is documented for CTNNA1 c.710A>G.
PP1	Not assessed	Not assessed: zero informative affected-relative or meiosis data are documented for CTNNA1 c.710A>G.
PP2	Not assessed	Not assessed: no calibrated CTNNA1 missense-spectrum evidence demonstrates high benign and low pathogenic missense rates for PP2.	PMID:25741868
PP3	Not met	Not met: REVEL 0.278 is below the PP3 supporting threshold of 0.644, and no calibrated BayesDel cutoff or CTNNA1-specific rule is available.	revel bayesdel
PP4	Not assessed	Not assessed: no patient phenotype or highly specific disease feature is documented for this exact CTNNA1 variant.	clinvar PMID:25394175 PMID:34043773 PMID:35957908 PMID:34326862
PP5	Not met	Not met: ClinVar reports zero expert-panel submissions and no exact-variant Pathogenic or Likely pathogenic expert-panel classification.	clinvar
BA1	Not met	Not met: maximum reported allele frequency is 0.0003502627, far below the generic BA1 stand-alone threshold of 0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: maximum reported allele frequency is 0.0003502627, below the supplied generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: no homozygotes were observed in gnomAD v2.1, v4.1, or the available non-cancer population subsets.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated variant-specific functional assay or preserved-function result was available for CTNNA1 p.Tyr237Cys.
BS4	Not assessed	Not assessed: no affected relatives lacking CTNNA1 c.710A>G or other informative non-segregation data are documented.
BP1	Not assessed	Not assessed: CTNNA1 loss-of-function evidence is present, but a primarily truncating disease spectrum required for BP1 is not established.	PMID:25741868
BP2	Not assessed	Not assessed: no individual-level cis/trans phase or pathogenic-variant pairing is documented for this CTNNA1 variant.	clinvar PMID:25741868
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.710A>G in CTNNA1 is a missense substitution predicted to produce NP_001894.2:p.(Tyr237Cys). 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, supporting: REVEL 0.278 meets the generic BP4 supporting threshold of <=0.29 from the ClinGen SVI calibration.	revel bayesdel
BP5	Not assessed	Not assessed: no alternative pathogenic molecular cause is documented in an affected individual carrying this CTNNA1 variant.	clinvar
BP6	Not met	Not met: the only Benign ClinVar assertion is a single-submitter laboratory result, not an exact-variant expert-panel classification.	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.710A>G in CTNNA1 is a missense substitution predicted to produce NP_001894.2:p.(Tyr237Cys). 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

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.