About GALNT12
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
GALNT12 c.-28C>T, p.?
Classification
Uncertain significance
Variant description:
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.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_024642.5:c.-28C>T is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency = 0.00327% (1/30,612 alleles) and gnomAD v4.1 allele frequency = 0.00435% (48/1,104,678 alleles), both well below the 0.1% threshold for PM2 under generic ACMG/AMP rules. Zero homozygotes observed.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
48 / 1,104,678 alleles
gnomAD v4.1: 48 / 1,104,678 alleles. Recorded AF 4.34516e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.26669e-05; MAF= 0.00327%, 1/30612 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.52146e-05; MAF= 0.00652%, 1/15334 alleles, homozygotes = 0).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 8 not met · 8 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_024642.5:c.-28C>T is a 5' UTR variant in GALNT12. It is present at extremely low frequency in gnomAD (v2.1 AF=0.00327%, v4.1 AF=0.00435%), meeting PM2 at supporting level.
SpliceAI predicts no splicing impact (max delta score = 0.00), but this single line of computational evidence is insufficient to meet PP3 or BP4 thresholds. REVEL and BayesDel scores are unavailable as the variant does not alter an amino acid.
This variant is absent from ClinVar and has not been reported in the published literature. No functional studies, case-control data, cosegregation data, or de novo observations are available.
PVS1 is not applicable as c.-28C>T is a 5' UTR substitution rather than a null variant (nonsense, frameshift, canonical splice, initiation codon, or exon deletion) eligible under the ClinGen SVI framework.
BS2 is not applicable for this gene: GALNT12 is a moderate-penetrance adult-onset cancer predisposition gene, and observation in healthy population controls does not constitute strong evidence against pathogenicity.
The only criterion met is PM2 (supporting). All other assessed criteria are either not met, not assessed due to insufficient evidence, or not applicable. This yields a classification of Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 generic rules.
No criteria match.
Met · 1
PM2 SupportingNM_024642.5:c.-28C>T is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency = 0.00327% (1/30,612 alleles) and gnomAD v4.1 allele frequency = 0.00435% (48/1,104,678 alleles), both well below the 0.1% threshold for PM2 under generic ACMG/AMP rules. Zero homozygotes observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=3.27e-05 (1/30612
- 0 hom)
- gnomAD v4.1 AF=4.35e-05 (48/1104678
- both <0.1% PM2 cutoff.
Sources
Not met · 8 · evaluated, threshold not reached
PS2 No de novo observation with confirmed maternity and paternity has been reported for NM_024642.5:c.-28C>T in ClinVar or the published literature. Details ▾Hide ▴
Evidence considered
- ClinVar contains zero submissions with de novo origin for this variant or any GALNT12 variant.
Still missing
- Trio sequencing data would be required to assess PS2
- unlikely to be available for a low-penetrance adult-onset cancer gene.
Sources
PM6 No de novo observation (without maternity/paternity confirmation) has been reported for NM_024642.5:c.-28C>T in ClinVar or the published literature. Details ▾Hide ▴
Evidence considered
- ClinVar contains zero de novo submissions for this variant
- dbSNP search also negative for de novo annotation.
Still missing
- De novo observations are unlikely for a moderate-penetrance adult-onset cancer predisposition variant.
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel scores are unavailable as the variant is in the 5' UTR and does not alter an amino acid. No in silico evidence supports a damaging functional consequence. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta=0.00 (no splice impact)
- REVEL/BayesDel/HCI prior not available for 5' UTR variant.
Still missing
- 5' UTR-specific in silico predictors (e.g.
- promoter disruption algorithms) could provide additional computational evidence.
Sources
PP5 NM_024642.5:c.-28C>T is absent from ClinVar. No reputable source (clinical diagnostic laboratory, expert panel) has reported this variant as pathogenic with supporting evidence that is unavailable to the evaluating laboratory. Details ▾Hide ▴
BA1 The allele frequency of NM_024642.5:c.-28C>T in gnomAD (v2.1: 0.00327%; v4.1: 0.00435%) is well below the 1% threshold for BA1 under generic ACMG/AMP rules. This variant is not a common polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD AF (0.00327% v2.1
- 0.00435% v4.1) << 1% BA1 threshold.
Sources
BS1 The allele frequency of NM_024642.5:c.-28C>T in gnomAD (v2.1: 0.00327%; v4.1: 0.00435%) is well below the 0.3% threshold for BS1 under generic ACMG/AMP rules. The variant frequency is not greater than expected for a moderate-penetrance cancer predisposition gene. Details ▾Hide ▴
Evidence considered
- gnomAD AF (0.00327% v2.1
- 0.00435% v4.1) << 0.3% BS1 threshold.
Sources
BP4 Multiple lines of computational evidence suggesting no impact are not available. SpliceAI predicts no splicing impact (max delta = 0.00), which is one line of evidence. However, REVEL and BayesDel scores are unavailable for this 5' UTR variant, precluding a second independent line of computational evidence. BP4 requires multiple lines. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta=0.00
- REVEL/BayesDel unavailable (no amino acid change)
- insufficient for 'multiple lines'.
Still missing
- Additional computational predictors specific to 5' UTR/regulatory variants would be needed for BP4 to be met.
Sources
BP6 NM_024642.5:c.-28C>T is absent from ClinVar. No reputable source has reported this variant as benign. Details ▾Hide ▴
Not assessed · 8 · no assessment recorded
PS3 No well-established functional studies demonstrating a damaging effect for NM_024642.5:c.-28C>T are available. No luciferase reporter assays, transcription factor binding studies, or other in vitro/in vivo functional characterization of the c.-28 position in GALNT12 has been identified. Details ▾Hide ▴
Evidence considered
- Exploratory literature search found no publications testing c.-28C>T specifically
- no functional data in evidence_brief.
Still missing
- Functional studies (e.g.
- promoter luciferase assay
- electrophoretic mobility shift assay) evaluating the impact of c.-28C>T on GALNT12 expression are needed.
PS4 No case-control study comparing the prevalence of NM_024642.5:c.-28C>T in affected individuals versus controls has been published. Population frequency alone without a case-control comparison is insufficient for PS4. Details ▾Hide ▴
Evidence considered
- No published odds ratio or statistical enrichment in colorectal cancer or other GALNT12-associated cancer cohorts.
Still missing
- Case-control studies comparing c.-28C>T frequency in colorectal cancer patients vs. healthy controls are needed.
PP1 No family cosegregation data are available for NM_024642.5:c.-28C>T. No published pedigrees testing this variant in families with colorectal cancer or other GALNT12-associated phenotypes have been identified. Details ▾Hide ▴
Evidence considered
- No ClinVar submissions with cosegregation data
- no published family studies identified.
Still missing
- Cosegregation analysis in families with colorectal cancer carrying c.-28C>T would be informative.
PP4 No patient-specific phenotype or family history data were provided for assessment. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No case-level phenotypic data available.
Still missing
- Detailed patient phenotype and family history are required to assess PP4.
BS3 No well-established functional studies demonstrating no damaging effect for NM_024642.5:c.-28C>T are available. No in vitro or in vivo assays evaluating the impact of this 5' UTR variant on GALNT12 expression or function have been identified. Details ▾Hide ▴
Evidence considered
- No functional studies testing c.-28C>T identified
- no luciferase or promoter assay data.
Still missing
- Functional studies demonstrating wild-type-like expression from the c.-28T allele are needed to assess BS3.
BS4 No family segregation data demonstrating lack of cosegregation with disease are available for NM_024642.5:c.-28C>T. No published family studies have reported on the segregation pattern of this variant. Details ▾Hide ▴
Evidence considered
- No published family studies with non-segregation data for this variant.
Still missing
- Family studies demonstrating absence of cosegregation with colorectal cancer would be needed for BS4.
BP2 No data are available on whether NM_024642.5:c.-28C>T has been observed in trans with a pathogenic variant in GALNT12 (relevant for a fully penetrant dominant disorder) or in cis with a pathogenic variant (relevant for a recessive disorder). GALNT12 is not a fully penetrant dominant gene, making BP2 applicability uncertain. Details ▾Hide ▴
Evidence considered
- No trans/cis configuration data available
- GALNT12 has moderate penetrance.
Still missing
- Phase information with known GALNT12 pathogenic variants would be needed.
BP5 No data are available on whether NM_024642.5:c.-28C>T has been observed in a case with an alternate molecular basis for disease. No case-level data were provided. Details ▾Hide ▴
Evidence considered
- No case-level data available to identify an alternate molecular cause.
Still missing
- Case data identifying an alternate pathogenic variant explaining the phenotype would be needed.
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_024642.5:c.-28C>T is a 5' UTR substitution and does not fall into any null-variant category (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, or exon deletion) eligible for PVS1 under the ClinGen SVI framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is in the 5' UTR (c.-28 position)
- variant_bucket='other' per PVS1 variant assessment
- apply_generic_pvs1_framework=false.
Sources
PS1 N/APS1 requires the same amino acid change as a previously established pathogenic variant. NM_024642.5:c.-28C>T is a 5' UTR variant with no resultant amino acid change (NP_078918.3:p.(=)). Details ▾Hide ▴
Evidence considered
- 5' UTR variant
- no amino acid change
- PS1 semantics do not apply.
PM1 N/APM1 requires location in a mutational hotspot or critical, well-established functional domain. The c.-28 position is in the 5' UTR of GALNT12; no mutational hotspot or established functional domain (e.g., active site, catalytic domain) has been defined for this region. Details ▾Hide ▴
Evidence considered
- 5' UTR position -28 is not within any characterized functional domain
- Cancer Hotspots does not list this residue as significant.
PM3 N/APM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. GALNT12 is not established as a recessive cancer predisposition gene; colorectal cancer risk associated with GALNT12 follows a moderate-penetrance autosomal dominant pattern. Details ▾Hide ▴
Evidence considered
- GALNT12 is not a recessive disorder gene.
PM4 N/APM4 applies to protein length changes due to in-frame deletions/insertions in non-repeat regions or stop-loss variants. NM_024642.5:c.-28C>T is a single-nucleotide substitution in the 5' UTR and does not alter protein length. Details ▾Hide ▴
Evidence considered
- Substitution variant in 5' UTR
- no protein length alteration.
PM5 N/APM5 requires a different pathogenic missense change at the same amino acid residue. NM_024642.5:c.-28C>T is a 5' UTR variant with no amino acid change; no residue-based comparator assessment is possible. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json confirms no classic same-residue PM5 semantics
- 0 same-residue candidates identified.
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense variants are a common mechanism of disease. NM_024642.5:c.-28C>T is a 5' UTR variant, not a missense variant. Details ▾Hide ▴
Evidence considered
- 5' UTR variant
- no amino acid substitution to evaluate under PP2.
BS2 N/ABS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. GALNT12 is associated with moderate-penetrance, adult-onset colorectal cancer predisposition. Observation in apparently healthy adults in gnomAD does not constitute strong evidence against pathogenicity for a gene with incomplete and age-dependent penetrance. Details ▾Hide ▴
Evidence considered
- GALNT12 is a moderate-penetrance adult-onset cancer gene
- not a fully penetrant early-onset disorder
- BS2 semantics do not apply.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_024642.5:c.-28C>T is a 5' UTR variant, not a missense variant. Details ▾Hide ▴
Evidence considered
- 5' UTR variant
- no amino acid substitution to evaluate under BP1.
BP3 N/ABP3 applies to in-frame deletions or insertions in a repetitive region without a known function. NM_024642.5:c.-28C>T is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
Evidence considered
- Substitution variant
- BP3 is for in-frame indels in repetitive regions.
BP7 N/ABP7 applies to synonymous (silent) coding variants for which splicing prediction algorithms predict no impact. NM_024642.5:c.-28C>T is a 5' UTR variant, not a synonymous coding variant. Details ▾Hide ▴
Evidence considered
- 5' UTR variant
- not a synonymous/silent coding variant
- BP7 does not apply.
PS5 N/APS5 requires a different pathogenic nucleotide change at the same position as an established pathogenic missense variant. NM_024642.5:c.-28C>T is a 5' UTR variant with no resultant amino acid, and there is no known pathogenic variant at this position. Details ▾Hide ▴
Evidence considered
- 5' UTR variant
- no amino acid change
- PS5 semantics do not apply.
Identifiers
- Gene
- GALNT12
- Transcript
- NM_024642.5
- Coding (HGVS c.)
- NM_024642.5:c.-28C>T
- Protein (HGVS p.)
- NP_078918.3:p.?
- GRCh38
- chr9:98807671 C>T
- GRCh37
- chr9:101569953 C>T
Gene diagram
Every interpreted variant in GALNT12, mapped onto the exon structure of NM_024642.5. Select a row to find it on the plot.
GALNT12NM_024642.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in GALNT12
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
48 / 1,104,678 alleles
AF 4.35e-05 · 0 homozygotes · FAF 3.98e-05
gnomAD v2.1
1 / 30,612 alleles
AF 3.27e-05 · 0 homozygotes
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 4.3e-05 · 48 / 1,104,678 alleles · 0 hom · FAF 4e-05
| European (non-Finnish)47 / 908,646 | 5.2e-05 |
| Remaining individuals1 / 36,278 | 2.8e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 3.3e-05 · 1 / 30,612 alleles · 0 hom
| European (non-Finnish)1 / 15,334 | 6.5e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.34516e-05; MAF= 0.00435%, 48/1104678 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.17253e-05; MAF= 0.00517%, 47/908646 alleles, homozygotes = 0); grpmax FAF= 3.985e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.26669e-05; MAF= 0.00327%, 1/30612 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.52146e-05; MAF= 0.00652%, 1/15334 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel scores are unavailable as the variant is in the 5' UTR and does not alter an amino acid. No in silico evidence supports a damaging functional consequence. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta=0.00 (no splice impact)
- REVEL/BayesDel/HCI prior not available for 5' UTR variant.
Still missing
- 5' UTR-specific in silico predictors (e.g.
- promoter disruption algorithms) could provide additional computational evidence.
Sources
BP4 Multiple lines of computational evidence suggesting no impact are not available. SpliceAI predicts no splicing impact (max delta = 0.00), which is one line of evidence. However, REVEL and BayesDel scores are unavailable for this 5' UTR variant, precluding a second independent line of computational evidence. BP4 requires multiple lines. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta=0.00
- REVEL/BayesDel unavailable (no amino acid change)
- insufficient for 'multiple lines'.
Still missing
- Additional computational predictors specific to 5' UTR/regulatory variants would be needed for BP4 to be met.
Sources
BP7 N/ABP7 applies to synonymous (silent) coding variants for which splicing prediction algorithms predict no impact. NM_024642.5:c.-28C>T is a 5' UTR variant, not a synonymous coding variant. Details ▾Hide ▴
Evidence considered
- 5' UTR variant
- not a synonymous/silent coding variant
- BP7 does not apply.
Statement
In silico
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.
gnomAD v4.1
48 / 1,104,678 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_024642.5%3Ac.-28C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-101569953-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-98807671-C-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_024642.5%3Ac.-28C…
- OncoKB ↗www.oncokb.org/gene/GALNT12/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=GALNT12+c.-28C%3ET
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 4.34516e-05; MAF= 0.00435%, 48/1104678 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.17253e-05; MAF= 0.00517%, 47/908646 alleles, homozygotes = 0); grpmax FAF= 3.985e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.26669e-05; MAF= 0.00327%, 1/30612 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.52146e-05; MAF= 0.00652%, 1/15334 alleles, homozygotes = 0).
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).