Variant classification summary

NM_001903.5:c.347G>A

CTNNA1 · NP_001894.2:p.(Cys116Tyr) · NM_001903.5

GRCh37: chr5:138145772 G>A · GRCh38: chr5:138810083 G>A

Gene: CTNNA1 Transcript: NM_001903.5

Final call

VUS

PM2 supporting PP1 supporting BP4 supporting

Variant details

Gene

CTNNA1

Transcript

NM_001903.5

Protein

NP_001894.2:p.(Cys116Tyr)

gnomAD AF

2.168522715585235e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): highest population allele frequency is 0.01349%, below the 0.1% rare-variant threshold.

2

PP1 (Supporting): the exact variant is reported in three affected members of one family (PMID:33435129), consistent with segregation.

3

BP4 (Supporting): SpliceAI predicts no splice impact (max delta 0.00, below the 0.2 threshold).

4

Overall classification: VUS - the one pathogenic-supporting and one benign-supporting combination meets no Likely Pathogenic or Likely Benign threshold under generic ACMG/AMP 2015 rules.

Final determination: Generic ACMG/AMP 2015 combination rules require thresholds not reached here (only 1 PP-level and 1 BP-level criterion met), 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	Not applicable: this missense change triggers no null-variant mechanism such as nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic variant producing the identical p.Cys116Tyr change was available.
PS2	Not assessed	Not assessed: no parental genotypes were provided to confirm a de novo occurrence.	PMID:25741868
PS3	Not assessed	Not assessed: no validated functional assay data for this variant were available.
PS4	Not assessed	Not assessed: no case-control enrichment or prevalence analysis for this variant was identified.	PMID:33435129
PM1	Not assessed	Not assessed: no gene-specific CTNNA1 domain map was available to place residue 116 in a critical functional domain.
PM2	Met	Met (supporting): highest population allele frequency is 0.01349%, below the 0.1% rare-variant threshold.	gnomad_v4 gnomad_v2 gnomad_canada
PM3	Not assessed	Not assessed: no affected proband is documented with this variant in trans with a pathogenic CTNNA1 variant.	clinvar generic_acmg_combination_rules
PM4	N/A	Not applicable: this missense substitution causes no protein length change, which PM4 requires.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no established pathogenic missense at codon 116 with a different amino acid substitution was available.	pm5_candidates
PM6	Not assessed	Not assessed: no parental testing was reported to support an assumed de novo occurrence.	PMID:25741868
PP1	Met	Met (supporting): the exact variant is reported in three affected members of one family (PMID:33435129).	PMID:33435129 PMID:25741868
PP2	Not assessed	Not assessed: no missense-constraint or gene-mechanism data were available for CTNNA1.
PP3	Not met	Not met: SpliceAI max delta 0.00 is far below the 0.2 splice-impact threshold.	spliceai revel bayesdel
PP4	Not assessed	Not assessed: familial comitant esotropia is not sufficiently specific for a CTNNA1-associated disorder.	clinvar PMID:33435129
PP5	Not assessed	Not assessed: no ClinVar expert-panel pathogenic assertion exists for this exact variant.	clinvar
BA1	Not met	Not met: highest population allele frequency 0.01349% is far below the 1% BA1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada
BS1	Not met	Not met: highest population allele frequency 0.01349% is below the 0.3% BS1 threshold.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no homozygous carriers or well-phenotyped unaffected adult carriers were documented.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no functional assay data demonstrating normal activity for this variant were available.
BS4	Not assessed	Not assessed: no affected non-carriers or unaffected carriers were documented to demonstrate non-segregation.	PMID:33435129 PMID:25741868
BP1	Not assessed	Not assessed: no evidence establishes that loss-of-function is the primary CTNNA1 disease mechanism.
BP2	Not assessed	Not assessed: the variant is not documented in cis or trans with a pathogenic CTNNA1 variant.	clinvar generic_acmg_combination_rules
BP3	N/A	Not applicable: BP3 applies only to in-frame indels in repetitive regions, not to missense substitutions.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): SpliceAI predicts no splice impact (max delta 0.00, below the 0.2 threshold).	spliceai revel bayesdel
BP5	Not assessed	Not assessed: no independent molecular diagnosis explains the tested phenotype.
BP6	Not assessed	Not assessed: no ClinVar expert-panel benign assertion exists for this exact variant.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants, and this is a missense substitution.	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.