Variant classification summary

NM_024642.5:c.-28C>T

GALNT12 · NP_078918.3:p.? · NM_024642.5

GRCh37: chr9:101569953 C>T · GRCh38: chr9:98807671 C>T

Gene: GALNT12 Transcript: NM_024642.5

Final call

VUS

PM2 supporting

Variant details

Gene

GALNT12

Transcript

NM_024642.5

Protein

NP_078918.3:p.?

gnomAD AF

4.345157593434467e-05 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

5

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.

6

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	NM_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).	pvs1_generic_framework
PS1	N/A	PS1 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.(=)).
PS2	Not met	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.	clinvar
PS3	Not assessed	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.
PS4	Not assessed	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.
PS5	N/A	PS5 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.
PM1	N/A	PM1 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.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 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.
PM6	Not met	No de novo observation (without maternity/paternity confirmation) has been reported for NM_024642.5:c.-28C>T in ClinVar or the published literature.	clinvar
PP1	Not assessed	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.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai
PP4	Not assessed	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.
PP5	Not met	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.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	N/A	BS2 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.
BS3	Not assessed	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.
BS4	Not assessed	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.
BP1	N/A	BP1 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.
BP2	Not assessed	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.
BP3	N/A	BP3 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.
BP4	Not met	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.	spliceai
BP5	Not assessed	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.
BP6	Not met	NM_024642.5:c.-28C>T is absent from ClinVar. No reputable source has reported this variant as benign.	clinvar
BP7	N/A	BP7 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.
PM3	N/A	PM3 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.
PM4	N/A	PM4 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.

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