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.
No pathogenic criterion marked as applied in the recorded assessment.
No benign criterion marked as applied in the recorded assessment.
With no ClinGen VCEP for GALNT12, generic ACMG/AMP 2015 rules applied: no criterion was met (gnomAD AF 2.8e-05; REVEL 0.607 in gray zone), so the variant is classified as VUS.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 45 / 1,612,678 alleles. Recorded AF 2.79039e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 1.98815e-05; MAF= 0.00199%, 5/251490 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000123031; MAF= 0.01230%, 2/16256 alleles, homozygotes = 0); grpmax FAF= 2.132e-05.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).
Recorded REVEL score: 0.607. Refer to the recorded PP3/BP4 rationale for interpretation.
4 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
No standalone functional evidence summary is recorded in evidence_summary.functional.
This variant has previously been reported in somatic cancers (COSMIC; COSV66663279, n = 3 times).
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: 0 met · 5 not met · 19 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No ClinGen VCEP/CSPEC exists for GALNT12 (case_summary.json cspec.found=false; vcep_materials.json note='no cspec url available'); generic ACMG/AMP 2015 definitions were used as the governing framework for this group.
Automated same-residue/same-change comparator harvesting (pm5_candidates.json) was explicitly skipped by the upstream pipeline rather than executed and negative, so PS1 and PM5 remain not_assessed rather than not_met.
The only hotspot check available (cancerhotspots.org) is a somatic cancer resource, returned negative, but cannot address germline PM1 domain/mutational-cluster criteria for this variant; no domain/structural data was found for GALNT12 residue 154.
No GALNT12 gene-level missense constraint metrics (gnomAD Z-score/o-e ratio) or curated missense-vs-truncating mechanism statement were present in the bundle, precluding assessment of PP2 and BP1.
GALNT12 has no ClinGen VCEP specification (cspec.found = false, vcep_materials.final_classification_framework.found = false); generic ACMG/AMP 2015 framework applies for PS3/BS3.
The case evidence bundle (prefetch.json, evidence.json, literature_pass.json, vcep_materials.json) contains no functional/biochemical assay results for this variant; the two retrieved full-text papers are ACMG/Sherloc methodology references, not variant-specific functional studies.
Both PS3 and BS3 are returned as not_assessed due to absence of any qualifying functional evidence in the case materials.
No GALNT12 ClinGen VCEP CSPEC PP3/BP4 lookup was available for this case; the generic ACMG/AMP in-silico calibration (generic_acmg_combination_rules) was applied instead.
The variant is a missense substitution, so only REVEL was used per the lab's mechanism-matching rule (missense -> REVEL only; splice-path/SpliceAI reserved for intronic, synonymous, or non-canonical-splice-position variants).
REVEL = 0.607 falls in the defined gray zone [0.250, 0.750], so neither PP3 nor BP4 is met.
BayesDel (0.252221) was not used because no verified published calibration threshold for BayesDel is available to this pipeline.
This variant is not synonymous, so BP7 is not applicable and was not assessed.
No GALNT12-specific VCEP/CSPEC framework was retrieved; generic ACMG/AMP population rules were applied.
The variant is rare but not absent: population data support neither BA1 nor BS1, and the observed alleles prevent PM2.
No individual-level healthy adult phenotype evidence was available for BS2.
No criteria match.
PM2 is not met because the exact variant is present in multiple population datasets rather than absent or consistently undetected. gnomAD v4.1 identifies 45 alternate alleles among 1,612,678 alleles (AF 2.79039e-05), gnomAD v2.1 identifies 5/251,490 alleles (AF 1.98815e-05), and gnomAD-Canada identifies 2/18,418 alleles (AF 0.0001085894), with zero homozygotes in each dataset.
Generic ACMG/AMP 2015 PM2: variant absent from or extremely rare in population databases; this exact variant is observed in several population datasets, so PM2 is not met.
NM_024642.5:c.460C>T is a missense substitution (NP_078918.3:p.(Arg154Trp)) in GALNT12. No GALNT12 ClinGen VCEP CSPEC was found for this case (cspec.found=false, gene_vcep_dir=null), so the lab's generic ACMG/AMP in-silico calibration rule (generic_acmg_combination_rules) applies: for a missense variant, evaluate REVEL only and do not fall back to the SpliceAI-based splice-path rule even though this variant also has a SpliceAI score, and do not combine the two predictors. REVEL score = 0.607 falls within the defined gray zone [0.250-0.750], which is neither the PP3 threshold (>0.750) nor the BP4 threshold (<0.250). Therefore PP3 is not met. BayesDel score (0.252221) exists in evidence but per this pipeline's calibration policy has no verified published threshold and is not used for PP3/BP4. SpliceAI max delta (0.312) is present but is explicitly excluded from consideration for this missense variant per the governing rule, which reserves the SpliceAI path for intronic/synonymous/non-canonical-splice-position variants only.
generic_acmg_missense_revel_gray_zone
The variant is far below the generic ACMG/AMP BA1 threshold of greater than 5% population frequency. gnomAD v4.1 reports an overall allele frequency of 2.79039e-05 (45/1,612,678 alleles), with the highest reported population frequency in African/African American individuals of 7.99574e-05; gnomAD v2.1 and gnomAD-Canada show similarly rare frequencies. BA1 is therefore not met.
Generic ACMG/AMP 2015 BA1: allele frequency >5% supports BA1; frequencies well below this threshold do not meet BA1.
The observed population frequency does not appear higher than expected for a rare Mendelian disease allele: the maximum observed frequency is 2.79039e-05 overall in gnomAD v4.1, 3.467e-05 by group FAF, and 0.0001703 in the small gnomAD-Canada non-Finnish group. These values are not evidence of a common or excess allele. A GALNT12-specific disease prevalence, penetrance, and maximum credible allele-frequency threshold were not available, so BS1 cannot be strengthened beyond this negative assessment and should receive human review if a disease-specific threshold is later established.
Generic ACMG/AMP 2015 BS1: allele frequency is greater than expected for the disorder; application requires a disease-specific expected-frequency context when available.
Same generic ACMG missense-path calibration as PP3: REVEL score = 0.607 is within the gray zone [0.250, 0.750], above the BP4 threshold of <0.250. Therefore BP4 is not met. As with PP3, BayesDel (0.252221) is not a validated predictor for this pipeline and SpliceAI (max delta 0.312) is not applicable because this is a missense variant governed by the REVEL-only rule, not the splice-path rule.
generic_acmg_missense_revel_gray_zone
No ClinGen VCEP/CSPEC exists for GALNT12 (case_summary.json cspec.found=false; vcep_materials.json note='no cspec url available'), so generic ACMG applies. PS1 requires a different nucleotide change at the same codon that results in the identical amino acid change (p.Arg154Trp) already established as pathogenic/likely pathogenic. The pm5_candidates.json artifact, which harvests same-residue ClinVar comparator variants, explicitly declined to run ('eligible_for_classic_pm5_search': false, reason: unable to confirm classic same-residue semantics safely') and returned zero candidates, so no same-amino-acid-change comparator data is available in this case bundle to evaluate PS1.
No case-specific evidence documents a confirmed de novo occurrence of NM_024642.5:c.460C>T (p.Arg154Trp) in the proband, parental genotypes, maternity/paternity, or phenotype consistency. The consolidated case-evidence bundle contains no proband or trio testing result sufficient to assess PS2.
No functional/biochemical assay data (e.g., in vitro glycosyltransferase activity assay, complementation study, or other validated functional characterization) for NM_024642.5:c.460C>T (p.Arg154Trp) in GALNT12 was found anywhere in the case bundle. GALNT12 has no ClinGen VCEP-specific PS3 specification, so generic ACMG/AMP applies, which still requires a validated assay with appropriate controls. The two full-text publications available in this case (PMID:25741868, PMID:26467025) are general ACMG classification methodology papers (the original ACMG/AMP 2015 guideline and the Sherloc scoring system paper) and do not report any variant-specific functional assay results for this variant.
No usable case-control enrichment dataset was identified for the exact variant NM_024642.5:c.460C>T (NP_078918.3:p.Arg154Trp). The available record contains no affected-case versus control counts, odds ratio, or statistical significance, so PS4 cannot be assessed.
Generic ACMG/AMP PS4 requires statistically significant enrichment in affected individuals compared with controls; no VCEP specification was available.
No GALNT12 VCEP/CSPEC-defined mutational hotspot or critical functional domain map is available. The only automated hotspot check performed (cancerhotspots.org, a somatic cancer hotspot resource) returned 'no_result' / 'found': false with evidence_sentence 'This variant does not lie in a statistically significant hotspot,' but this is a somatic cancer database and not a germline structural/functional domain source, so it cannot establish or exclude PM1 for a germline colorectal-cancer-susceptibility gene. No UniProt/Pfam domain boundary or structural (X-ray/cryo-EM) data for the GALNT12 ppGalNAc-T catalytic or lectin domains, and no data on residue 154's proximity to a catalytic motif, is present anywhere in the bundle. COSMIC shows only 3 somatic observations at this variant (not indicative of an established hotspot).
No applicable GALNT12-specific VCEP/CSPEC framework is available, so generic ACMG/AMP criteria were used. The case bundle contains no affected-proband observations, family-level genotypes, phase information, or pathogenic/likely pathogenic variant documented in trans with NM_024642.5:c.460C>T (p.Arg154Trp). Therefore PM3 cannot be assessed.
Generic ACMG/AMP PM3: pathogenic variants in trans with the variant under evaluation can support recessive disease; phase and phenotype/inheritance context must be established.
PM5 requires a different missense change at the same residue (Arg154) previously established as pathogenic/likely pathogenic. pm5_candidates.json explicitly did not perform the classic same-residue comparator search for this case ('eligible_for_classic_pm5_search': false; 'candidates': []; recommendation.level': 'not_applicable' with instruction to not apply PM5 from this artifact alone), so no alternate-amino-acid-at-residue-154 pathogenic comparator data is available.
No case-specific evidence documents a suspected de novo occurrence of NM_024642.5:c.460C>T (p.Arg154Trp) without adequate parental confirmation. The consolidated case-evidence bundle contains no family history, parental testing, maternity/paternity, or proband phenotype evidence sufficient to assess PM6.
No affected or unaffected relatives carrying or lacking NM_024642.5:c.460C>T (p.Arg154Trp) are reported, and no informative meioses or segregation counts are available. Therefore, cosegregation with disease cannot be assessed.
PP2 requires the variant to be missense in a gene with (a) a low rate of benign missense variation and (b) missense changes as a common/established mechanism of disease. No gene-level missense constraint metric (e.g., gnomAD missense Z-score or observed/expected ratio) for GALNT12 is present anywhere in the bundle. pvs1_gene_context.json establishes only that loss-of-function/germline literature supports a GALNT12-truncating-variant disease mechanism ('lof_mechanism_supported': true) for the associated basal cell carcinoma predisposition phenotype; it does not characterize missense variation as a common disease mechanism, and no missense-specific mechanism data is present.
The case bundle does not provide a patient phenotype or a highly specific phenotype matching a GALNT12-associated disorder for this exact variant. ClinVar condition labels include colorectal cancer susceptibility but the exact submission record provides no patient-level phenotype documentation, so PP4 cannot be applied.
Generic ACMG/AMP PP4 may be used when the patient's phenotype or family history is highly specific for a disease with a single-gene etiology; no VCEP specification was available.
PP5 is not triggered. The exact ClinVar record for NM_024642.5:c.460C>T has no expert-panel submission; all four submissions are clinical-testing, single-submitter assertions classified as uncertain significance. Therefore, there is no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification eligible for PP5.
Apply PP5 only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; exclude ordinary laboratory submissions, aggregate labels, and non-expert assertions.
No homozygous carriers are reported in gnomAD v2.1, gnomAD v4.1, or gnomAD-Canada, and no case-specific healthy adult genotype/phenotype observations were provided. The absence of homozygotes is not positive BS2 evidence for this heterozygous missense variant. BS2 cannot be assessed from the available evidence.
Generic ACMG/AMP 2015 BS2: the variant is observed in a healthy adult individual for a disorder with complete or near-complete penetrance; suitable individual-level phenotype and inheritance context are required.
No functional/biochemical assay data showing normal/wild-type-like activity for NM_024642.5:c.460C>T (p.Arg154Trp) in GALNT12 was found anywhere in the case bundle. GALNT12 has no ClinGen VCEP-specific BS3 specification, so generic ACMG/AMP applies. The two full-text publications available (PMID:25741868, PMID:26467025) are general ACMG classification methodology papers and contain no variant-specific functional results for this variant.
No reliable non-segregation data are documented. The case bundle does not identify informative affected relatives who lack the variant, nor does it provide phenotype, age, penetrance, or testing-quality information needed to interpret an apparent non-segregation observation.
BP1 requires established gene-specific evidence that missense variants are not a recognized mechanism of disease (i.e., disease is driven primarily by truncating/LOF variants) with a correspondingly low rate of pathogenic missense variation. While pvs1_gene_context.json documents that GALNT12 germline disease association is supported through an LOF mechanism, this alone does not meet the bar for BP1, which requires a quantitative/gene-specific determination (e.g., via VCEP specification or missense variant pathogenicity rate) that missense changes as a class are not disease-causing in this gene; no such quantitative or VCEP-defined threshold is present in the bundle.
No applicable GALNT12-specific VCEP/CSPEC framework is available, so generic ACMG/AMP criteria were used. The case bundle contains no reliable co-occurrence observation showing NM_024642.5:c.460C>T (p.Arg154Trp) with a pathogenic variant in trans or with a pathogenic variant in cis in an affected or unaffected individual, and no phase information is available. Therefore BP2 cannot be assessed.
Generic ACMG/AMP BP2: observed co-occurrence with a pathogenic variant in trans or cis may support benign evidence when the relevant phase, phenotype, and inheritance context are established.
No evidence was identified that the variant was found in a patient with a clearly established molecular diagnosis of an alternative disease that explains the presentation. The case bundle contains no relevant coexisting molecular diagnosis or clinical alternative-diagnosis documentation, so BP5 cannot be assessed.
Generic ACMG/AMP BP5 may be considered when a variant is found in a patient with an alternate molecular diagnosis that explains the phenotype; no VCEP specification was available.
BP6 is not triggered. The exact ClinVar record has no expert-panel submission and all four laboratory submissions classify the variant as uncertain significance. There is no exact-variant ClinVar expert-panel Benign or Likely benign classification eligible for BP6.
Apply BP6 only for an exact-variant ClinVar expert-panel Benign or Likely benign classification; exclude ordinary laboratory submissions, aggregate labels, and non-expert assertions.
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.460C>T in GALNT12 is a missense substitution predicted to produce NP_078918.3:p.(Arg154Trp). 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
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.460C>T in GALNT12 is a missense substitution predicted to produce NP_078918.3:p.(Arg154Trp). 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
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.460C>T in GALNT12 is a missense substitution predicted to produce NP_078918.3:p.(Arg154Trp). 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
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_024642.5:c.460C>T in GALNT12 is a missense substitution predicted to produce NP_078918.3:p.(Arg154Trp). 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.
deterministic_prefilter: requires_synonymous
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 |
|---|
| African/African American6 / 75,040 | 8e-05 |
| Admixed American2 / 60,030 | 3.3e-05 |
| European (non-Finnish)35 / 1,178,604 | 3e-05 |
| South Asian2 / 91,042 | 2.2e-05 |
| African/African American2 / 16,256 | 0.00012 |
| South Asian1 / 30,616 | 3.3e-05 |
| European (non-Finnish)2 / 113,766 | 1.8e-05 |
This variant is present in gnomAD v4.1 (AF= 2.79039e-05; MAF= 0.00279%, 45/1612678 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 7.99574e-05; MAF= 0.00800%, 6/75040 alleles, homozygotes = 0); grpmax FAF= 3.467e-05.
This variant is present in gnomAD v2.1 (AF= 1.98815e-05; MAF= 0.00199%, 5/251490 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000123031; MAF= 0.01230%, 2/16256 alleles, homozygotes = 0); grpmax FAF= 2.132e-05.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).
NM_024642.5:c.460C>T is a missense substitution (NP_078918.3:p.(Arg154Trp)) in GALNT12. No GALNT12 ClinGen VCEP CSPEC was found for this case (cspec.found=false, gene_vcep_dir=null), so the lab's generic ACMG/AMP in-silico calibration rule (generic_acmg_combination_rules) applies: for a missense variant, evaluate REVEL only and do not fall back to the SpliceAI-based splice-path rule even though this variant also has a SpliceAI score, and do not combine the two predictors. REVEL score = 0.607 falls within the defined gray zone [0.250-0.750], which is neither the PP3 threshold (>0.750) nor the BP4 threshold (<0.250). Therefore PP3 is not met. BayesDel score (0.252221) exists in evidence but per this pipeline's calibration policy has no verified published threshold and is not used for PP3/BP4. SpliceAI max delta (0.312) is present but is explicitly excluded from consideration for this missense variant per the governing rule, which reserves the SpliceAI path for intronic/synonymous/non-canonical-splice-position variants only.
generic_acmg_missense_revel_gray_zone
Same generic ACMG missense-path calibration as PP3: REVEL score = 0.607 is within the gray zone [0.250, 0.750], above the BP4 threshold of <0.250. Therefore BP4 is not met. As with PP3, BayesDel (0.252221) is not a validated predictor for this pipeline and SpliceAI (max delta 0.312) is not applicable because this is a missense variant governed by the REVEL-only rule, not the splice-path rule.
generic_acmg_missense_revel_gray_zone
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_024642.5:c.460C>T in GALNT12 is a missense substitution predicted to produce NP_078918.3:p.(Arg154Trp). 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.
deterministic_prefilter: requires_synonymous
SpliceAI predicts possible splice impact for this variant (max delta score = 0.31). REVEL score = 0.607. BayesDel score = 0.252221.
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
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= 2.79039e-05; MAF= 0.00279%, 45/1612678 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 7.99574e-05; MAF= 0.00800%, 6/75040 alleles, homozygotes = 0); grpmax FAF= 3.467e-05.
This variant is present in gnomAD v2.1 (AF= 1.98815e-05; MAF= 0.00199%, 5/251490 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000123031; MAF= 0.01230%, 2/16256 alleles, homozygotes = 0); grpmax FAF= 2.132e-05.
This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories). (ClinVarID = 241514)
SpliceAI predicts possible splice impact for this variant (max delta score = 0.31). REVEL score = 0.607. BayesDel score = 0.252221.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66663279, n = 3 times).
This variant does not lie in a statistically significant hotspot.