LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-20
Case ID: NM_004655.4_c.2013_2024del_20260820_040958
Framework: ACMG/AMP 2015
Variant classification summary

NM_004655.4:c.2013_2024del

AXIN2  · NP_004646.3:p.(Thr672_Arg675del)  · NM_004655.4
GRCh37: chr17:63532554 ACGGGGGGTGGTG>A  ·  GRCh38: chr17:65536436 ACGGGGGGTGGTG>A
Gene: AXIN2 Transcript: NM_004655.4
Final call
Benign
BA1 stand-alone benign BP3 supporting BP4 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
AXIN2
Transcript
NM_004655.4
Protein
NP_004646.3:p.(Thr672_Arg675del)
gnomAD AF
0.003934509534167457 (v4.1)
ClinVar
Benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
BA1 (stand-alone benign): gnomAD v4.1 African/African American allele frequency 7.33% exceeds the 5% BA1 threshold.
2
BP3 (supporting): in-frame 12-nucleotide deletion falls in a repetitive 6-G homopolymer region without known function, outside all conserved domains.
3
BP4 (supporting): SpliceAI max delta 0.019 predicts no splice-altering impact (threshold ~0.2).
4
Overall classification: Benign, per generic ACMG/AMP 2015 fallback combination rules driven by BA1 at stand-alone strength.
Final determination: Generic ACMG/AMP 2015 fallback: BA1 met (>5% population frequency) is sufficient alone for Benign, reinforced by two supporting benign criteria and no conflicting pathogenic evidence.
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 in-frame 12-nucleotide deletion removes four amino acids without a premature stop, so no null-variant mechanism applies.
pvs1_generic_framework generic_acmg_combination_rules
PS1 N/A Not applicable: the in-frame deletion produces no single amino acid change to compare against a previously pathogenic missense.
generic_acmg_combination_rules
PS2 Not assessed Not assessed: no proband phenotype or parental genotype data were available to evaluate a confirmed de novo occurrence.
PMID:25741868
PS3 Not assessed Not assessed: no validated functional assay data addressing this variant were available.
PS4 Not assessed Not assessed: no variant-specific case-control or cohort enrichment data were provided.
PM1 N/A Not applicable: no altered residue exists to evaluate for mutational hotspot or critical-domain membership.
generic_acmg_combination_rules
PM2 Not met Not met: gnomAD v4.1 African/African American allele frequency is 7.33%, far above rarity thresholds for PM2.
gnomad_v4 gnomad_v2 gnomad_canada
PM3 Not assessed Not assessed: no proband observation or phase result establishes this variant in trans with a pathogenic allele.
clinvar PMID:25741868
PM4 Not met Not met: the in-frame deletion lies in a repetitive 6-G homopolymer region, which PM4 explicitly excludes.
PMID:25741868 spliceai gnomad_v4 gnomad_v2 clinvar
PM5 N/A Not applicable: no missense change exists at this residue to compare against a different pathogenic missense.
generic_acmg_combination_rules
PM6 Not assessed Not assessed: no parental genotype data were available to evaluate an assumed de novo occurrence.
PMID:25741868
PP1 Not assessed Not assessed: no genotyped relatives or informative meioses were provided, so co-segregation could not be evaluated.
PMID:25741868
PP2 N/A Not applicable: PP2 concerns missense variants, and this variant is an in-frame deletion.
generic_acmg_combination_rules
PP3 Not met Not met: SpliceAI max delta 0.019, far below the ~0.2 threshold for predicted splice-altering impact.
spliceai
PP4 Not assessed Not assessed: no phenotype-to-gene specificity evidence was provided for the tested individual.
PP5 Not met Not met: the ClinVar record carries no pathogenic or likely pathogenic expert-panel assertion.
clinvar
BA1 Met Met (stand-alone benign): gnomAD v4.1 African/African American allele frequency 7.33% exceeds the 5% BA1 threshold.
gnomad_v4 gnomad_v2 PMID:25741868
BS1 Not met Not met: BA1 already applies at stand-alone strength, superseding the lower-strength BS1 frequency criterion.
gnomad_v4 gnomad_v2 PMID:25741868
BS2 Not assessed Not assessed: homozygotes are reported, but individual phenotypes, ages, and disease status are not documented.
gnomad_v4 gnomad_v2 gnomad_canada
BS3 Not assessed Not assessed: no benign-consistent functional assay result for this variant was available.
BS4 Not assessed Not assessed: no informative family phenotypes and genotypes were provided to establish lack of segregation.
PMID:25741868
BP1 N/A Not applicable: BP1 concerns missense variants, and this variant is an in-frame deletion.
generic_acmg_combination_rules
BP2 Not assessed Not assessed: no second AXIN2 variant or phase result was provided to evaluate cis/trans configuration.
clinvar PMID:25741868
BP3 Met Met (supporting): in-frame 12-nucleotide deletion in a repetitive 6-G homopolymer region outside all known functional domains.
PMID:25741868 spliceai gnomad_v4 gnomad_v2 clinvar
BP4 Met Met (supporting): SpliceAI max delta 0.019, well below the ~0.2 threshold for splice-altering impact.
spliceai
BP5 Not assessed Not assessed: no evidence that an alternate molecular diagnosis fully explains the phenotype was provided.
BP6 Not met Not met: the ClinVar record carries no benign or likely benign expert-panel assertion.
clinvar
BP7 N/A Not applicable: BP7 applies to synonymous variants, and this variant is an in-frame deletion.
generic_acmg_combination_rules
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