Variant classification summary

NM_024642.5:c.123T>G

GALNT12 · NP_078918.3:p.(Arg41=) · NM_024642.5

GRCh37: chr9:101570103 T>G · GRCh38: chr9:98807821 T>G

Gene: GALNT12 Transcript: NM_024642.5

Final call

VUS

PM2 supporting BP7 supporting

Variant details

Gene

GALNT12

Transcript

NM_024642.5

Protein

NP_078918.3:p.(Arg41=)

gnomAD AF

9.593264760676824e-07 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): extremely rare in gnomAD (v4.1 total AF 0.0001%), far below the 0.1% threshold.

2

BP7 (Supporting): synonymous variant with no predicted splice impact (SpliceAI max delta 0.00 vs the 0.2 threshold); conservation prong flagged for human review.

3

Variant of Uncertain Significance: one supporting pathogenic (PM2) and one supporting benign (BP7) criterion meet no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule.

Final determination: Generic ACMG/AMP 2015 fallback combination rules: PM2 (supporting) + BP7 (supporting) does not meet any Benign (1 BA1; 2 BS), Likely Benign (1 BS + 1 BP; 2 BP), Likely Pathogenic, or Pathogenic threshold, 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	Not applicable: this is a synonymous substitution (p.Arg41=), so no null-variant mechanism such as nonsense-mediated decay applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: the variant is synonymous (p.Arg41=), so there is no amino acid change to compare with a previously established pathogenic variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband genotype or parental testing data were available to evaluate a confirmed de novo occurrence.	generic_acmg_combination_rules clinvar
PS3	Not assessed	Not assessed: no functional assay evidence for this variant was available to evaluate a damaging effect.	generic_acmg_combination_rules
PS4	Not assessed	Not assessed: no case-control or cohort data for this variant were available to evaluate enrichment in affected individuals.	clinvar gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM1	N/A	Not applicable: the variant is synonymous (p.Arg41=), so no altered residue exists to assess for a mutational hotspot or critical domain.	generic_acmg_combination_rules
PM2	Met	Met (supporting): gnomAD v4.1 total allele frequency is 0.0001% (1/1,042,398 alleles), far below the 0.1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not met	Not met: no pathogenic variant in trans is documented, and no recessive inheritance framework applies to this variant.	generic_acmg_combination_rules pvs1_gene_context clinvar
PM4	N/A	Not applicable: no protein length change occurs, as this is a synonymous substitution (p.Arg41=).	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue, so there is nothing to compare against a known pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband-parent trio data or de novo observation of this variant were available.	generic_acmg_combination_rules clinvar
PP1	Not assessed	Not assessed: no affected family members were tested, so no segregation data were available.	generic_acmg_combination_rules clinvar
PP2	N/A	Not applicable: this is a synonymous substitution (p.Arg41=), so the gene's missense-variant constraint is irrelevant.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.00 shows no predicted splice impact, far below the 0.2 threshold.	spliceai pvs1_variant_assessment generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no phenotype or family-history data were available for carriers of this variant.	clinvar generic_acmg_combination_rules
PP5	Not met	Not met: no ClinVar expert-panel classification of pathogenic exists for this variant; only ordinary laboratory submissions.	clinvar generic_acmg_combination_rules
BA1	Not met	Not met: highest population allele frequency is 0.000096% (gnomAD v4.1), far below the 1% benign threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: highest robust population frequency is 0.0057% (AMR), below the 0.3% threshold.	gnomad_v2 gnomad_v4
BS2	N/A	Not applicable: the gene's phenotype is adult-onset cancer susceptibility with reduced penetrance, not a fully penetrant early-onset disorder.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no functional studies demonstrating absence of a damaging effect were available.	generic_acmg_combination_rules spliceai
BS4	Not assessed	Not assessed: no affected family members were tested, so lack of segregation could not be evaluated.	generic_acmg_combination_rules clinvar
BP1	N/A	Not applicable: this is a synonymous substitution (p.Arg41=), so the truncating-variant mechanism is irrelevant.	generic_acmg_combination_rules
BP2	Not met	Not met: no second pathogenic variant or phase data show this variant in cis or trans with a pathogenic allele.	generic_acmg_combination_rules clinvar
BP3	N/A	Not applicable: the variant does not alter protein length, so the repetitive-region in-frame criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: the only computational prediction (SpliceAI max delta 0.00) is counted under BP7, leaving no independent line of evidence.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband case data were available to evaluate an alternative molecular basis for disease.	clinvar generic_acmg_combination_rules
BP6	Not met	Not met: no ClinVar expert-panel benign classification exists; the 'Likely benign' label comes from ordinary laboratory submissions.	clinvar generic_acmg_combination_rules
BP7	Met	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.	spliceai pvs1_variant_assessment generic_acmg_combination_rules

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