LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-09-18
Case ID: NM_004655.4_c.1530G_A_20260918_184251
Framework: ACMG/AMP 2015
Variant classification summary

NM_004655.4:c.1530G>A

AXIN2  · NP_004646.3:p.(Thr510=)  · NM_004655.4
GRCh37: chr17:63533624 C>T  ·  GRCh38: chr17:65537506 C>T
Gene: AXIN2 Transcript: NM_004655.4
Final call
Likely Benign
BS3 supporting BP7 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
AXIN2
Transcript
NM_004655.4
Protein
NP_004646.3:p.(Thr510=)
gnomAD AF
0.004454238094765961 (v4.1)
ClinVar
Benign
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Likely Benign: BS3 (supporting) - patient RNA RT-PCR showed c.1530G>A present at the same proportion as genomic DNA, indicating no splicing alteration.
2
Likely Benign: BP7 (supporting) - synonymous p.(Thr510=) with SpliceAI max delta 0.001, far below the 0.2 significant-impact cutoff.
3
No pathogenic criterion met - PS3 negative functional assay, PS4 no case enrichment, PM2 frequency 30-45x its cutoff, and no de novo, segregation or expert-panel evidence exists.
4
Benign not reached - maximum population frequency 0.553% stays below both the 1% BS1 and 5% BA1 thresholds.
Final determination: Under the generic ACMG/AMP 2015 fallback rules, two supporting benign criteria (BS3 and BP7) yield Likely Benign.
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_004655.4:c.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). 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 N/A PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_004655.4:c.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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
PS2 Not met Not met: no de novo occurrence of c.1530G>A is reported, and the carrier study states parental DNA samples were unavailable, so parentage was never tested.
PMID:25741868 PMID:16941501 clinvar
PS3 Not met Not met: patient RNA RT-PCR across exons 3-7 showed c.1530G>A at the same proportion as genomic DNA, i.e. no splicing alteration.
PMID:16941501 PMID:26467025 PMID:25741868 spliceai
PS4 Not met Not met: three case series each report this variant in one affected individual with no odds ratio or significant case-control enrichment, while gnomAD v4.1 shows AF 0.445% with 21 homozygotes.
PMID:25741868 PMID:16941501 PMID:29114927 PMID:30555066 gnomad_v2 gnomad_v4 clinvar generic_acmg_combination_rules final_classification_framework
PM1 N/A PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_004655.4:c.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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
PM2 Not met Not met: allele frequency 0.285%-0.445% in gnomAD is roughly 30-45x the 0.0001 supporting PM2 threshold.
gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868 PMID:29114927 PMID:16941501 PMID:30555066 generic_acmg_combination_rules
PM3 Not met Not met: no affected proband carries c.1530G>A in trans with a pathogenic AXIN2 variant; the only phase-resolved observation is in cis (PMID:16941501).
PMID:25741868 PMID:16941501 PMID:29114927 PMID:30555066 pvs1_gene_context gnomad_v2 gnomad_v4
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_004655.4:c.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). 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 N/A PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_004655.4:c.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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
PM6 Not met Not met: no report describes c.1530G>A as arising de novo, and without parental DNA even an assumed de novo event cannot be claimed.
PMID:25741868 PMID:16941501 clinvar
PP1 Not met Not met: zero informative meioses - no genotyped pedigree for c.1530G>A is reported, so co-segregation with disease is unestablished.
PMID:25741868 PMID:16941501 PMID:29114927 PMID:30555066
PP2 N/A PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_004655.4:c.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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
PP3 N/A Not applicable: c.1530G>A is synonymous, p.(Thr510=), outside PP3's missense and intronic/splice-region scope.
PP4 Not assessed Not assessed: the case contains no proband phenotype, HPO terms or family history, so PP4's requirement for a phenotype highly specific to a single-gene disease cannot be evaluated.
PMID:25741868 PMID:29114927 PMID:30555066 PMID:16941501 clinvar generic_acmg_combination_rules final_classification_framework
PP5 Not met Not met: the exact-variant ClinVar record (ClinVarID 136481, 19 laboratory submissions) has zero expert-panel submissions, so no Pathogenic expert-panel source exists.
clinvar PMID:25394175 PMID:25741868 generic_acmg_combination_rules final_classification_framework
BA1 Not met Not met: highest population frequency is 0.553% in gnomAD v4.1 European (non-Finnish), far below the 5% BA1 stand-alone threshold.
gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868 generic_acmg_combination_rules
BS1 Not met Not met: maximum population frequency is 0.553% (gnomAD v4.1 non-Finnish European) versus the 1% BS1 threshold.
gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868 generic_acmg_combination_rules
BS2 Not met Not met: gnomAD homozygotes exist (21 in v4.1) but lack the documented healthy-adult status and early-age full penetrance that BS2 requires.
gnomad_v2 gnomad_v4 PMID:25741868
BS3 Met Met at supporting strength: RT-PCR of the carrier's RNA showed c.1530G>A present in the same proportion as genomic DNA, indicating no splicing alteration.
PMID:16941501 PMID:25741868 spliceai
BS4 Not met Not met: no genotyped pedigree for c.1530G>A is reported, so non-segregation with disease in affected relatives has not been demonstrated.
PMID:25741868 PMID:16941501 PMID:29114927 PMID:30555066
BP1 N/A BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_004655.4:c.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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
BP2 Not met Not met: no pathogenic AXIN2 variant occurs in cis or trans; the only phased observation places c.1530G>A in cis with the non-pathogenic p.Asn412Ser (PMID:16941501).
PMID:25741868 PMID:16941501 gnomad_v2 gnomad_v4
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_004655.4:c.1530G>A in AXIN2 is a synonymous (silent) substitution predicted to produce NP_004646.3:p.(Thr510=). 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 N/A Not applicable: c.1530G>A is synonymous, p.(Thr510=), outside BP4's missense and intronic/splice-region scope.
BP5 Not met Not met: no alternate molecular basis is documented for the proband, and the variant's reported carrier was APC-, MMR- and MUTYH-negative.
PMID:16941501 PMID:25741868 generic_acmg_combination_rules
BP6 Not met Not met: ClinVar's Benign/Likely benign label for this variant comes from 19 clinical laboratories with no expert-panel submission, which cannot trigger BP6.
clinvar PMID:25741868 generic_acmg_combination_rules final_classification_framework
BP7 Met Met, supporting: synonymous p.(Thr510=) with SpliceAI max delta 0.001, far below the 0.2 significant-impact cutoff.
spliceai PMID:16941501 PMID:25741868 clinvar gnomad_v4
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