No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.GALNT12 encodes a member of the UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase family, enzymes that initiate O-linked glycosylation by transferring N-acetylgalactosamine (GalNAc) to serine or threonine residues on proteins. These glycosylation modifications are important for the proper function of many cellular proteins. Mutations in this gene are associated with increased susceptibility to colorectal cancer, indicating a role in colorectal cancer predisposition.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met (supporting): gnomAD v4.1 total allele frequency is 0.0001% (1/1,042,398 alleles), far below the 0.1% threshold.
Met (supporting): synonymous variant with no splice impact (SpliceAI max delta 0.00, below the 0.2 threshold). Flagged for human review: the nucleotide-conservation prong could not be verified.
No ClinGen VCEP specification exists for GALNT12, so generic ACMG/AMP 2015 rules applied; PM2 (supporting) plus BP7 (supporting) meets no combination threshold, yielding Variant of Uncertain Significance.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 1 / 1,042,398 alleles. Recorded AF 9.59326e-07. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 4.03942e-05; MAF= 0.00404%, 1/24756 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.0026738; MAF= 0.26738%, 1/374 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
1 Likely benign · 1 Benign. ClinVar API review status: criteria provided, single submitter.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 8 not met · 9 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Framework: no ClinGen CSPEC/VCEP specification exists for GALNT12 (cspec.found=false; vcep_materials note 'no cspec url available'; gene_vcep_dir=null), so the generic ACMG/AMP 2015 framework (Richards et al., PMID 25741868, via generic_acmg_combination_rules) governs this case.
No de novo or segregation evidence is present for NM_024642.5:c.123T>G: literature_pass.json reports 0 PMIDs, fulltext_map.json is empty, and ClinVar VCV001758097 consists of two single-submitter entries (Ambry 'Likely benign' germline 2021-02-03; Myriad 'Benign', origin unknown) with no criteria and no validated PMIDs.
PS2, PM6, PP1, and BS4 are all not_assessed: proband, parental, and family testing data are entirely absent from the bundle. None of these criteria can be met from population frequency or from another source's final classification (ClinVar Benign/Likely benign labels were not used to infer any criterion).
gnomAD v2.1 (AF 4.04e-05; AMR 0.27%) and v4.1 (AF 9.59e-07; AMR 5.72e-05) population presence is not BS4 evidence; non-segregation requires documented lack of segregation in affected family members, which is unavailable here.
Governing framework: no ClinGen CSPEC/VCEP or gene-specific framework for GALNT12 (cspec found=false; vcep_materials.json empty; final_classification_framework source=generic_acmg_fallback); generic ACMG/AMP (Richards et al. 2015, PMID 25741868) applies to PS3/BS3.
PS3: not_assessed - no well-established functional studies supportive of a damaging effect for c.123T>G (p.Arg41=) were found (0 PMIDs in literature pass, empty fulltext_map, no files in publications/, no functional leads in ClinVar submissions).
BS3: not_assessed - no well-established functional studies demonstrating no damaging effect for c.123T>G (p.Arg41=); SpliceAI max delta 0.00 is in-silico only and does not meet BS3.
Neither PS3 nor BS3 contributes to the classification. The absence of functional evidence is a documented data gap, not evidence of benignity; any benign signal for this variant must come from other criteria groups (e.g., population/silico), not from the functional group.
ClinVar final classifications (Likely benign/Benign) were not used to infer PS3 or BS3, per adjudication rules forbidding inference of criteria from another source's final classification.
No case-control enrichment or phenotype-specificity evidence is available for the synonymous variant NM_024642.5:c.123T>G (p.Arg41=) in GALNT12; PS4 and PP4 are not assessable (0 PMIDs; no proband, cohort, or case-level data).
ClinVar VCV001758097 contains only ordinary single-submitter laboratory classifications (Ambry Genetics Likely benign, Myriad Genetics Benign; 1-star review status) with zero expert-panel submissions, so PP5 and BP6 are not met despite the aggregate Likely benign label.
No alternate molecular basis or co-occurrence data exist for this variant, so BP5 is not assessable.
Governing framework: no ClinGen CSPEC found for GALNT12 (cspec.found=false) and no local custom gene framework present (vcep_materials empty, no gene_vcep_files), so generic ACMG/AMP 2015 (Richards et al., PMID 25741868; source_registry key 'generic_acmg_combination_rules') governs all criteria in this group.
Variant under assessment: NM_024642.5:c.123T>G, NP_078918.3:p.(Arg41=) — a synonymous, non-splice-impacting variant (SpliceAI max delta 0.00) in GALNT12 exon 1; ClinVar VCV001758097 with two 1-star submissions (Ambry Likely benign, Myriad Benign) that carry no PMIDs and were not used as criterion evidence.
Allelic evidence inventory: the case evidence bundle contains no proband phenotype, no family/segregation data, no zygosity or phase data, no second GALNT12 variant, and no compound-heterozygote observations; literature_pass reports total_pmids=0 and fulltext_map is empty, so no publication-based allelic evidence exists.
PM3 not met: no recessive-disease framework is established for this variant (pvs1_gene_context inheritance list empty; germline LoF context is consistent with dominant cancer susceptibility) and no pathogenic variant in trans is documented.
BP2 not met: no observation of this variant in trans (fully penetrant dominant) or in cis with a pathogenic variant exists in any case material.
Because both allelic criteria rest on observations (phase, co-occurrence) that are absent rather than contradicted, the determinations are negative (not_met) with high confidence, and the specific missing data types are listed in gaps_remaining for potential future re-evaluation if family/phase testing data are added.
Governing framework: no ClinGen CSPEC or gene-specific VCEP exists for GALNT12 (cspec found=false; gene_vcep_dir null; framework_mode generic_acmg); generic ACMG/AMP 2015 (Richards et al., PMID 25741868) governs all criteria in this group. No VCEP pre-assignment of PP3/BP4/BP7 exists.
Variant class: NM_024642.5:c.123T>G is a synonymous variant (NP_078918.3:p.(Arg41=), consequence_class 'synonymous'); missense in-silico predictors (REVEL, BayesDel, aGVGD) are not applicable because no amino acid substitution occurs, and none returned a score (revel found=false, bayesdel found=false).
Splice path: SpliceAI max delta score = 0.00 with all four delta scores 0.0 -> no predicted effect on existing splice sites and no predicted creation of new splice sites; this provides no PP3 support and constitutes the evidence for the splice prong of BP7.
No-double-count rule: the single available in-silico prediction (SpliceAI 0.00) is counted once, under BP7 (the synonymous-variant-specific criterion); it is not additionally counted for BP4, so BP4 is not independently met.
PP3 not_met: no computational line supports a deleterious effect (splice path negative; missense path not applicable).
BP7 met at supporting strength: synonymous variant, no predicted splice impact, outside canonical splice consensus; the 'not highly conserved' prong is unverified (no conservation score captured) and flagged needs_human_review.
No criterion was inferred from any other source's final classification (ClinVar, gnomAD etc. were not used for PP3/BP4/BP7).
Governing framework: no ClinGen CSPEC and no gene-specific VCEP materials were retrieved for GALNT12 (cspec found=false, gene_vcep_dir=null, vcep_materials final_classification_framework found=false); generic ACMG/AMP 2015 fallback (Richards et al., PMID 25741868) governs, per generic_acmg_combination_rules.
Population evidence is limited to gnomAD v2.1 (genome-only, 24,756 alleles) and gnomAD v4.1 (genome-only within this capture, 1,042,398 alleles); gnomAD-Canada v1.0 query failed (HTTP 500).
The variant is extremely rare: total AF 0.004% (v2.1) and 0.0001% (v4.1), 0 homozygotes in both datasets; PM2 is met at supporting strength.
The v2.1 AMR AF of 0.267% (1/374 alleles) is a single-allele small-denominator artifact: v4.1 shows the same allele in AMR at 0.0057% (1/17,478). It is below both the BS1 (>0.3%) and BA1 (>1%) lab non-VCEP thresholds and is not replicated, so BA1 and BS1 are not met.
BS2 is not applicable: the GALNT12-associated phenotype is adult-onset, reduced-penetrance cancer susceptibility, failing the criterion's requirement of full penetrance at an early age; no homozygotes are observed regardless.
ClinVar submissions (Benign by Myriad, Likely benign by Ambry) are other laboratories' final classifications and were not used to infer any population criterion.
Net population-group contribution: PM2 supporting toward benign-leaning interpretation; no BA1/BS1/BS2 evidence.
No criteria match.
PM2 (supporting) is met: the variant is present at extremely low frequency in gnomAD, far below the lab non-VCEP threshold of 0.1%. gnomAD v4.1 (largest dataset, 1,042,398 alleles): total AF 9.59e-07 (0.0001%, 1/1,042,398 alleles), max subpopulation AF 0.0057% (AMR), 0 homozygotes. gnomAD v2.1: total AF 4.04e-05 (0.004%, 1/24,756 alleles), 0 homozygotes. Both total AFs are more than an order of magnitude below 0.1% regardless of which dataset is used, and no population subset exceeds 0.1% in v4.1. The single v2.1 AMR allele at 0.267% reflects a denominator of 374 alleles and is not a reliable population estimate (v4.1 AMR: 0.0057%); it does not undermine the extremely-low-frequency determination. PM2 is met at supporting strength.
PM2: absent or at extremely low frequency (<0.1%) in population databases for non-VCEP gene frameworks (generic ACMG/AMP 2015, PMID 25741868)
The variant is confirmed synonymous (NM_024642.5:c.123T>G; NP_078918.3:p.(Arg41=)) and does not fall in canonical splice consensus (pvs1_variant_assessment: canonical_splice_consensus false; c.123 lies within exon 1, c.-29 to c.371, well away from intron boundaries). SpliceAI predicts no splice impact: max delta score = 0.00 with all four delta scores 0.0 (DS_AL/DS_DL = no effect on existing acceptor/donor; DS_AG/DS_DG = no creation of new acceptor/donor splice sites), below the >=0.2 predicted-impact threshold of the SpliceAI publication (Jaganathan et al., Cell 2019; PMID 30661751). This satisfies the splice-impact prong of BP7 (no impact on splice consensus and no new splice site creation). Caveat: the 'nucleotide is not highly conserved' prong of BP7 could not be directly verified because no nucleotide conservation score (e.g., phyloP, GERP, PhastCons) was captured in the evidence bundle; BP7 is therefore applied at supporting strength with needs_human_review=true so a reviewer can confirm low conservation. Generic ACMG/AMP 2015 (Richards et al. 2015, PMID 25741868) governs; no ClinGen CSPEC/VCEP exists for GALNT12.
BP7 (Richards et al. 2015, PMID 25741868): A synonymous (silent) variant for which splicing prediction algorithms predict no impact on the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
PM3 (ACMG/AMP 2015, PMID 25741868) requires, for a recessive disorder, detection of the variant in trans with a pathogenic variant in an affected proband. Both prongs fail on the available evidence. (1) No recessive disease framework is established for GALNT12 in this case: no ClinGen CSPEC or local gene-specific framework exists (generic_acmg fallback), and pvs1_gene_context records an empty inheritance list with a germline loss-of-function mechanism context consistent with dominant cancer susceptibility; no evidence in the bundle supports a recessive inheritance mode for this variant. (2) No second GALNT12 variant, no zygosity data, and no phase information are present anywhere in the case-evidence bundle (case_summary, prefetch, evidence, clinvar submission audit, literature_pass): there is no documented pathogenic variant in trans, no compound-heterozygote observation, and no affected-proband allelic data. ClinVar submissions for VCV001758097 (Ambry 'Likely benign', Myriad 'Benign'; both 1-star, criteria provided/single submitter, no PMIDs, condition 'not specified') are final classifications from other submitters and were not used to infer this criterion. PM3 is therefore not met.
PM3: For recessive disorders, detected in trans with a pathogenic variant (Richards et al., ACMG/AMP 2015, PMID 25741868).
No calibrated computational evidence supports a deleterious effect. Splice path: SpliceAI max delta score = 0.00 with all four delta scores (DS_AG, DS_AL, DS_DG, DS_DL) = 0.0, i.e., no predicted impact on existing splice donor/acceptor sites and no predicted creation of new splice sites; this is far below the >=0.2 predicted splice-impact threshold recommended in the SpliceAI publication (Jaganathan et al., Cell 2019; PMID 30661751), so the splice path provides no PP3 support. Missense path: the variant is synonymous (NP_078918.3:p.(Arg41=)), so protein-level in-silico predictors (REVEL, BayesDel, aGVGD) are not applicable (no amino acid substitution); no REVEL or BayesDel score was retrieved (found=false in prefetch), and BayesDel has no verified published threshold available to this pipeline in any case. No ClinGen CSPEC/VCEP exists for GALNT12 (cspec found=false), so no gene-specific PP3/BP4 pre-assignment applies; generic ACMG/AMP 2015 PP3 definition (Richards et al. 2015, PMID 25741868) governs. No evidence was taken from any other source's final classification.
PP3 (Richards et al. 2015, PMID 25741868): Multiple lines of computational evidence support a deleterious effect on the gene or gene product (includes splice-impact and missense in-silico predictors).
PP5 (Richards et al. 2015, PMID:25741868) is applied only for an exact-variant ClinVar expert-panel classification of Pathogenic/Likely pathogenic. The ClinVar submission audit for VCV001758097 shows zero expert-panel submissions (expert_panel_submissions = 0); the two existing submissions are ordinary laboratory classifications (Ambry Genetics 'Likely benign', Myriad Genetics 'Benign', both 'criteria provided, single submitter', 1-star review status) with no validated PMIDs. Ordinary laboratory submissions and aggregate ClinVar labels never trigger PP5, so the criterion is definitively not met.
ACMG/AMP 2015 PP5 - reputable source (expert-panel classification required per pipeline policy)
BA1 requires an allele frequency above the benign-population threshold (lab non-VCEP operating threshold >1%; Richards et al. 2015 baseline BA1 >5%). The highest credible population AF for this variant is gnomAD v4.1 total AF 9.59e-07 (0.000096%, 1/1,042,398 alleles) and max subpopulation AF 5.72e-05 (0.0057%, AMR 1/17,478). gnomAD v2.1 total AF is 4.04e-05 (0.004%, 1/24,756 alleles). The only AF approaching a threshold is the v2.1 AMR figure of 0.267% (1/374 alleles), which is a single-allele small-denominator artifact not replicated in v4.1 (same allele at 0.0057% AMR) and remains below even the >1% lab threshold. BA1 is not met under any threshold considered.
BA1: allele frequency >1% in a large population database (lab non-VCEP operating threshold; Richards et al. 2015, PMID 25741868, baseline >5%)
BS1 requires an allele frequency greater than expected for the disorder (lab non-VCEP operating threshold >0.3%). gnomAD v4.1 total AF is 0.0001% and the highest robust subpopulation AF is 0.0057% (AMR). gnomAD v2.1 total AF is 0.004%. The v2.1 AMR AF of 0.267% (1/374 alleles) is below the 0.3% threshold and is a single-allele small-sample artifact: v4.1 shows the same AMR allele at 0.0057% (1/17,478). No population exceeds 0.3% in any dataset. For this adult-onset, reduced-penetrance colorectal cancer susceptibility gene, no disease-specific prevalence/penetrance calibration was retrievable, so the lab's default non-VCEP 0.3% threshold was applied; the variant does not meet it.
BS1: allele frequency >0.3% in a large population database (lab non-VCEP operating threshold; generic ACMG/AMP 2015, PMID 25741868)
BP2 (ACMG/AMP 2015, PMID 25741868) requires the variant to be observed in trans with a pathogenic variant in a fully penetrant dominant gene/disorder, or in cis with a pathogenic variant in any inheritance pattern. The required co-occurrence observation is entirely absent from this case: the evidence bundle contains no second pathogenic variant in GALNT12, no phase/zygosity data, no parental or family testing results, and no segregation observations for this synonymous variant (c.123T>G, p.(Arg41=)). ClinVar's two 1-star submissions (Likely benign and Benign, no PMIDs, non-expert-panel) provide no allelic-configuration evidence and, as final classifications from other submitters, were not used to infer this criterion. Literature pass found zero PMIDs (total_pmids=0), so no published observation of this variant in cis/trans with a pathogenic variant exists in the case materials. BP2 is therefore not met.
BP2: Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder; or observed in cis with a pathogenic variant in any inheritance pattern (Richards et al., ACMG/AMP 2015, PMID 25741868).
The only computational prediction available in this case is the SpliceAI result (max delta = 0.00, indicating no predicted splice impact). That single prediction is allocated to BP7, the synonymous-variant-specific criterion that directly consumes it (no-double-count rule), and is therefore not additionally counted toward BP4. Missense in-silico tools (REVEL, BayesDel, aGVGD) are not applicable to this synonymous variant (no protein change) and returned no scores. With no independent computational line, BP4 is not met. No ClinGen CSPEC/VCEP exists for GALNT12, so no gene-specific BP4 pre-assignment applies; generic ACMG/AMP 2015 BP4 definition (Richards et al. 2015, PMID 25741868) governs.
BP4 (Richards et al. 2015, PMID 25741868): Multiple lines of computational evidence suggest no impact on gene or gene product (includes splicing prediction algorithms).
BP6 (Richards et al. 2015, PMID:25741868) is applied only for an exact-variant ClinVar expert-panel classification of Benign/Likely benign. The ClinVar submission audit for VCV001758097 shows zero expert-panel submissions; the aggregate 'Likely benign' label (1-star review status) and the two single-submitter laboratory classifications (Ambry Genetics 'Likely benign', Myriad Genetics 'Benign') are ordinary laboratory assertions, which must never trigger BP6. The criterion is definitively not met.
ACMG/AMP 2015 BP6 - reputable source (expert-panel classification required per pipeline policy)
PS2 (de novo, paternity and maternity confirmed; Richards et al. 2015, PMID 25741868) cannot be evaluated because the case bundle contains no proband genotype/phenotype record, no parental testing results, and no de novo observation with confirmed parentage. literature_pass.json reports 0 PMIDs, fulltext_map.json is empty, and ClinVar VCV001758097 (two single-submitter entries: Ambry Genetics 'Likely benign' germline, and Myriad Genetics 'Benign'; neither with criteria or validated PMIDs) contains no de novo assertion. Absence of data is not evidence of absence, so the criterion is not_assessed rather than not_met.
PS2: De novo (paternity and maternity confirmed) - Richards et al. 2015 (PMID 25741868), generic ACMG/AMP fallback for GALNT12
No applicable VCEP/CSPEC or gene-specific functional assay framework exists for GALNT12 (cspec not found; vcep_materials.json empty; final_classification_framework found=false, source=generic_acmg_fallback), so generic ACMG/AMP (PMID 25741868) governs. PS3 requires well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product. No functional assay evidence for NM_024642.5:c.123T>G (p.Arg41=) is present anywhere in the case evidence bundle: literature_pass.json reports 0 PMIDs ('No PMIDs found across evidence sources'), fulltext_map.json is empty, the publications/ directory contains no files, and neither ClinVar submission (SCV002671546 Ambry Genetics 'Likely benign'; SCV007649057 Myriad Genetics 'Benign') carries any PMID, functional criterion lead, or assay description (validated_pmids=0, criterion_leads=[]). The variant is a synonymous change (p.Arg41=, exon 1), so any functional relevance would have to be established through RNA/splicing or protein-expression/enzymatic assays; none were located. With no functional studies available, PS3 cannot be evaluated and is returned as not_assessed with the evidence gap identified.
PS3 - Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (Richards et al. 2015, PMID 25741868).
PS4 (Richards et al. 2015, PMID:25741868) requires a statistically significant case-control enrichment of the variant in affected individuals. No case-control or cohort study data exist for NM_024642.5:c.123T>G (p.Arg41=) in GALNT12: the literature pass returned 0 PMIDs, ClinVar VCV001758097 contains no case-level or prevalence data (only two single-submitter laboratory classifications, Ambry Genetics 'Likely benign' and Myriad Genetics 'Benign', with no validated PMIDs), and the population resources document control frequencies only (gnomAD v2.1 total AF 4.04e-05, 1/24,756 alleles; gnomAD v4.1 total AF 9.59e-07, 1/1,042,398 alleles), which cannot substitute for case-control enrichment. PS4 is not assessable from the available evidence.
ACMG/AMP 2015 PS4 - case-control enrichment (PMID:25741868)
PM6 (de novo without confirmation of paternity and maternity; Richards et al. 2015, PMID 25741868) cannot be evaluated: there is no proband-parent trio data, no phenotype-consistency description, and no de novo observation of c.123T>G in any collected source. The literature pass identified 0 PMIDs and no full texts are available (fulltext_map.json is empty). ClinVar VCV001758097 provides only two single-submitter aggregate classifications with no criteria leads. The criterion is therefore not_assessed.
PM6: De novo (without confirmation of paternity and maternity) - Richards et al. 2015 (PMID 25741868), generic ACMG/AMP fallback for GALNT12
PP1 (cosegregation with disease in multiple affected family members; Richards et al. 2015, PMID 25741868) cannot be evaluated: no affected family members are tested or described in the bundle, no segregation/meiosis counts exist, and no phenotype consistency information is available. literature_pass.json found 0 PMIDs and ClinVar VCV001758097 entries provide no family or segregation data. The criterion is not_assessed because there is no segregation evidence of any kind.
PP1: Cosegregation with disease in multiple affected family members - Richards et al. 2015 (PMID 25741868), generic ACMG/AMP fallback for GALNT12
PP4 (Richards et al. 2015, PMID:25741868) requires the variant to be present in patients with a phenotype or family history highly specific for the gene's disease. No phenotype, family-history, or proband data are reported for carriers of NM_024642.5:c.123T>G: ClinVar lists no condition detail for the submissions (conditions 'not specified'), and no publication reports this exact variant in any GALNT12-associated phenotype (colorectal cancer susceptibility). PP4 is not assessable from the available evidence.
ACMG/AMP 2015 PP4 - phenotype/family history specificity (PMID:25741868)
BS3 requires well-established functional studies showing no damaging effect on protein function or splicing. No validated functional assay data for NM_024642.5:c.123T>G (p.Arg41=) exists in the case bundle: literature_pass.json found 0 PMIDs, fulltext_map.json is empty, the publications/ directory contains no files, and the ClinVar submissions (SCV002671546, SCV007649057) carry no PMIDs or criterion leads from which a functional study could be identified. SpliceAI reports max delta score 0.00 (no predicted splice impact), but this is an in-silico prediction, not a well-established functional study; under SVI PS3/BS3 calibration, in-silico predictors do not qualify as functional evidence for BS3 (splice in-silico evidence belongs to the BP4/BP7 domain), so it was consulted and explicitly excluded from BS3. With no functional assay demonstrating absence of a damaging effect, BS3 cannot be evaluated and is returned as not_assessed with the evidence gap identified. Absence of functional evidence must not be equated with evidence of benignity.
BS3 - Well-established functional studies show no damaging effect on protein function or splicing (Richards et al. 2015, PMID 25741868).
BS4 (lack of segregation in affected members of a family; Richards et al. 2015, PMID 25741868) cannot be evaluated. No affected family members were tested, so no non-segregation observation (affected relative lacking the variant, or variant failing to track with disease) exists. Population frequency from gnomAD (v2.1 total AF 4.04e-05; v4.1 total AF 9.59e-07) is not a substitute for BS4 - it pertains to frequency-based benign criteria (BA1/BS1) handled by other groups. Absence of segregation data must not be interpreted as evidence of non-segregation, so BS4 is not_assessed rather than not_met.
BS4: Lack of segregation in affected members of a family - Richards et al. 2015 (PMID 25741868), generic ACMG/AMP fallback for GALNT12
BP5 (Richards et al. 2015, PMID:25741868) applies when the variant is found in a case with an alternate molecular basis for the disease. No proband-level data exist for NM_024642.5:c.123T>G: no alternate-locus pathogenic variant, clinical case context, or segregation data are reported in any evidence source (0 PMIDs; ClinVar submissions carry no case or co-occurrence detail). BP5 is not assessable from the available evidence.
ACMG/AMP 2015 BP5 - alternate molecular basis (PMID:25741868)
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_024642.5:c.123T>G in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Arg41=). 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.
deterministic_prefilter: requires_null_variant_class
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_024642.5:c.123T>G in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Arg41=). 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.
deterministic_prefilter: requires_missense
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_024642.5:c.123T>G in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Arg41=). 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.
deterministic_prefilter: requires_missense
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_024642.5:c.123T>G in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Arg41=). 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.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
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_024642.5:c.123T>G in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Arg41=). 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.
deterministic_prefilter: requires_missense
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_024642.5:c.123T>G in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Arg41=). 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.
deterministic_prefilter: requires_missense
Generic ACMG/AMP 2015 BS2 requires observation of the variant in a healthy adult for a disorder with full penetrance expected at an early age. The GALNT12-associated phenotype is adult-onset cancer susceptibility with reduced penetrance, so the criterion's core premise (full penetrance at early age) is not satisfied and BS2 does not apply to this gene-disease context. Independently, no homozygous carriers are observed in gnomAD v2.1 or v4.1 (0 homozygotes in both), and gnomAD does not provide phenotype/age-verified healthy-adult status that would satisfy BS2 even if the criterion were considered applicable.
BS2: observed in a healthy adult for a recessive/dominant/X-linked disorder with full penetrance expected at an early age (Richards et al. 2015, PMID 25741868)
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_024642.5:c.123T>G in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Arg41=). 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.
deterministic_prefilter: requires_missense
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_024642.5:c.123T>G in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Arg41=). 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.
deterministic_prefilter: requires_repeat_region_indel
Every interpreted variant in GALNT12, mapped onto the exon structure of NM_024642.5. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Admixed American1 / 17,478 | 5.7e-05 |
| Admixed American1 / 374 | 0.0027 |
This variant is present in gnomAD v4.1 (AF= 9.59326e-07; MAF= 0.00010%, 1/1042398 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.72148e-05; MAF= 0.00572%, 1/17478 alleles, homozygotes = 0).
This variant is present in gnomAD v2.1 (AF= 4.03942e-05; MAF= 0.00404%, 1/24756 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.0026738; MAF= 0.26738%, 1/374 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
The variant is confirmed synonymous (NM_024642.5:c.123T>G; NP_078918.3:p.(Arg41=)) and does not fall in canonical splice consensus (pvs1_variant_assessment: canonical_splice_consensus false; c.123 lies within exon 1, c.-29 to c.371, well away from intron boundaries). SpliceAI predicts no splice impact: max delta score = 0.00 with all four delta scores 0.0 (DS_AL/DS_DL = no effect on existing acceptor/donor; DS_AG/DS_DG = no creation of new acceptor/donor splice sites), below the >=0.2 predicted-impact threshold of the SpliceAI publication (Jaganathan et al., Cell 2019; PMID 30661751). This satisfies the splice-impact prong of BP7 (no impact on splice consensus and no new splice site creation). Caveat: the 'nucleotide is not highly conserved' prong of BP7 could not be directly verified because no nucleotide conservation score (e.g., phyloP, GERP, PhastCons) was captured in the evidence bundle; BP7 is therefore applied at supporting strength with needs_human_review=true so a reviewer can confirm low conservation. Generic ACMG/AMP 2015 (Richards et al. 2015, PMID 25741868) governs; no ClinGen CSPEC/VCEP exists for GALNT12.
BP7 (Richards et al. 2015, PMID 25741868): A synonymous (silent) variant for which splicing prediction algorithms predict no impact on the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved.
No calibrated computational evidence supports a deleterious effect. Splice path: SpliceAI max delta score = 0.00 with all four delta scores (DS_AG, DS_AL, DS_DG, DS_DL) = 0.0, i.e., no predicted impact on existing splice donor/acceptor sites and no predicted creation of new splice sites; this is far below the >=0.2 predicted splice-impact threshold recommended in the SpliceAI publication (Jaganathan et al., Cell 2019; PMID 30661751), so the splice path provides no PP3 support. Missense path: the variant is synonymous (NP_078918.3:p.(Arg41=)), so protein-level in-silico predictors (REVEL, BayesDel, aGVGD) are not applicable (no amino acid substitution); no REVEL or BayesDel score was retrieved (found=false in prefetch), and BayesDel has no verified published threshold available to this pipeline in any case. No ClinGen CSPEC/VCEP exists for GALNT12 (cspec found=false), so no gene-specific PP3/BP4 pre-assignment applies; generic ACMG/AMP 2015 PP3 definition (Richards et al. 2015, PMID 25741868) governs. No evidence was taken from any other source's final classification.
PP3 (Richards et al. 2015, PMID 25741868): Multiple lines of computational evidence support a deleterious effect on the gene or gene product (includes splice-impact and missense in-silico predictors).
The only computational prediction available in this case is the SpliceAI result (max delta = 0.00, indicating no predicted splice impact). That single prediction is allocated to BP7, the synonymous-variant-specific criterion that directly consumes it (no-double-count rule), and is therefore not additionally counted toward BP4. Missense in-silico tools (REVEL, BayesDel, aGVGD) are not applicable to this synonymous variant (no protein change) and returned no scores. With no independent computational line, BP4 is not met. No ClinGen CSPEC/VCEP exists for GALNT12, so no gene-specific BP4 pre-assignment applies; generic ACMG/AMP 2015 BP4 definition (Richards et al. 2015, PMID 25741868) governs.
BP4 (Richards et al. 2015, PMID 25741868): Multiple lines of computational evidence suggest no impact on gene or gene product (includes splicing prediction algorithms).
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 9.59326e-07; MAF= 0.00010%, 1/1042398 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.72148e-05; MAF= 0.00572%, 1/17478 alleles, homozygotes = 0).
This variant is present in gnomAD v2.1 (AF= 4.03942e-05; MAF= 0.00404%, 1/24756 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.0026738; MAF= 0.26738%, 1/374 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 1758097)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.