NM_024642.5:c.567T>C

GALNT12 · NP_078918.3:p.(Asn189=) · NM_024642.5

GRCh37: chr9:101589059 T>C · GRCh38: chr9:98826777 T>C

Gene: GALNT12 Transcript: NM_024642.5

Final call

VUS

BP4 supporting

Variant details

Gene

GALNT12

Transcript

NM_024642.5

Protein

NP_078918.3:p.(Asn189=)

gnomAD AF

0.00045488338726152754 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

BP4 supporting: SpliceAI max delta 0.017 for synonymous c.567T>C is below the <=0.1 no-splice-impact cutoff, the sole met criterion.

PM2 not met: gnomAD v2.1 AF 0.00074 and v4.1 AF 0.00046 exceed the 0.0001 rarity threshold.

BA1/BS1 not met: highest ancestry-specific frequency 0.151% is ~33-fold below 5% and ~7-fold below 1%.

PP3 not met: SpliceAI max delta 0.017 is far below the >=0.2 supporting cutoff for a splice-altering effect.

PP5/BP6 not met: expert_panel_submissions = 0 for ClinVar VCV000416212, so no expert-panel assertion exists in either direction.

BS2 not met: the single gnomAD v4.1 homozygote cannot support a full-penetrance early-onset disorder, GALNT12-related risk being adult-onset and incompletely penetrant.

Final combination: 1 supporting benign criterion (BP4) is below the Likely Benign threshold of 2 BP or 1 BS + 1 BP, and no pathogenic rule is met, giving VUS.

Final determination: Under the generic ACMG/AMP 2015 rules, one supporting benign criterion (BP4) reaches neither Benign (BA1 or 2 BS) nor Likely Benign (1 BS + 1 BP, or 2 BP) and no pathogenic combination is met, so the variant is a 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	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.567T>C in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Asn189=). 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.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	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.567T>C in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Asn189=). 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.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband or parental genotype data are present in the case, so confirmed de novo status — PS2's required basis — cannot be established.	PMID:25741868
PS3	Not assessed	Not assessed: no functional assay of GALNT12 c.567T>C exists in any retrieved source, and the only functional-themed paper (PMID:25741868) never mentions the variant.	generic_acmg_combination_rules clinvar PMID:25741868
PS4	Not assessed	Not assessed: no case-control or affected-proband enrichment data exist for c.567T>C, and the only two papers retrieved are general ACMG/AMP framework documents.	clinvar PMID:25741868 PMID:28492532
PM1	N/A	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.567T>C in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Asn189=). 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.	generic_acmg_combination_rules
PM2	Not met	Not met: allele frequencies 0.00074 (gnomAD v2.1) and 0.000455 (v4.1) exceed the 0.0001 supporting-PM2 rarity threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
PM3	Not assessed	Not assessed: no phase data exists - no pathogenic variant reported in trans with c.567T>C, and GALNT12 inheritance is undocumented.	clinvar pvs1_gene_context PMID:25741868 generic_acmg_combination_rules
PM4	N/A	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.567T>C in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Asn189=). 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.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	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.567T>C in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Asn189=). 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.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband observation of c.567T>C exists, so even assumed de novo status — PM6's requirement — cannot be applied.	PMID:25741868
PP1	Not assessed	Not assessed: no pedigree or affected relatives were reported, leaving zero informative meioses for PP1 co-segregation assessment.	PMID:25741868
PP2	N/A	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.567T>C in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Asn189=). 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.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.017 is far below the >=0.2 PP3 supporting cutoff for this synonymous variant, which is scored on the splice path only.	spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or HPO terms are recorded, and the exact variant's ClinVar condition labels are only generic cancer-susceptibility entries.	clinvar PMID:25741868
PP5	Not met	Not met: all six ClinVar submissions for c.567T>C are from single clinical laboratories (expert_panel_submissions = 0), so no expert-panel pathogenic assertion exists.	clinvar
BA1	Not met	Not met: highest subpopulation frequency 0.151% (gnomAD v3.1 non-cancer Ashkenazi Jewish) is roughly 33-fold below the 5% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
BS1	Not met	Not met: highest observed frequency 0.151% (gnomAD v3.1 non-cancer Ashkenazi Jewish, 5/3,302) is about 7-fold below the 1% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules PMID:25741868
BS2	Not met	Not met: a single gnomAD v4.1 homozygote (European non-Finnish) cannot satisfy BS2, which requires early-onset, fully penetrant disease.	gnomad_v2 gnomad_v4 gnomad_canada PMID:25741868
BS3	Not assessed	Not assessed: no functional assay reports a benign effect for GALNT12 c.567T>C, and the ClinVar benign submissions cite no variant-level assay evidence.	generic_acmg_combination_rules clinvar PMID:25741868
BS4	Not assessed	Not assessed: no family members were genotyped, so no non-segregation observation exists to support BS4.	PMID:25741868
BP1	N/A	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.567T>C in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Asn189=). 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.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no cis/trans phase data exists for c.567T>C, so no pathogenic partner allele could be confirmed or excluded.	clinvar PMID:25741868 generic_acmg_combination_rules
BP3	N/A	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.567T>C in GALNT12 is a synonymous (silent) substitution predicted to produce NP_078918.3:p.(Asn189=). 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.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met at supporting strength: SpliceAI max delta 0.017 is at or below the <=0.1 no-splice-impact BP4 cutoff, counted once and not reused for BP7.	spliceai generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband-level data exist, and no alternate molecular cause of disease is documented for any carrier of c.567T>C.	clinvar
BP6	Not met	Not met: expert_panel_submissions = 0 for c.567T>C, so the Benign/Likely benign label rests on six ordinary clinical laboratories, not an expert panel.	clinvar
BP7	Not met	Not met: this synonymous variant's only supporting result, SpliceAI max delta 0.017, is already counted under BP4, and no conservation data is available.	spliceai PMID:25741868

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