Variant classification summary

NM_024642.5:c.1201C>T

GALNT12 · NP_078918.3:p.(Arg401Cys) · NM_024642.5

GRCh37: chr9:101599419 C>T · GRCh38: chr9:98837137 C>T

Gene: GALNT12 Transcript: NM_024642.5

Final call

VUS

BP4 supporting

Variant details

Gene

GALNT12

Transcript

NM_024642.5

Protein

NP_078918.3:p.(Arg401Cys)

gnomAD AF

1.7967203039307283e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP4 supporting: REVEL 0.214 is below the <=0.29 missense threshold.

2

VUS: BP4 alone does not meet the generic ACMG/AMP threshold for Likely Benign or Benign.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting benign criterion alone does not meet a benign or likely benign combination, so the final call is VUS.

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.1201C>T in GALNT12 is a missense substitution predicted to produce NP_078918.3:p.(Arg401Cys). 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	Not met	Not met: no independently reported pathogenic or likely pathogenic variant producing the same GALNT12 p.Arg401Cys amino-acid change was identified.	clinvar PMID:28944238
PS2	Not assessed	Not assessed: no documented de novo observation with confirmed maternity and paternity is available for c.1201C>T.
PS3	Not assessed	Not assessed: no variant-specific functional assay or validated damaging-effect result was reported for GALNT12 p.Arg401Cys.
PS4	Not assessed	Not assessed: the 1,231-case/93-control study did not explicitly report this variant, so no reliable variant-specific enrichment or case count is available.	PMID:28944238 clinvar
PM1	Not met	Not met: residue 401 is not reported in a statistically significant hotspot, and no approved GALNT12 critical-domain table is available.
PM2	Not met	Not met: gnomAD v4.1 East Asian AF is 1.11393e-04, exceeding the supplied PM2 threshold of 0.0001 despite a lower aggregate AF.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband, phase, or pathogenic-in-trans observation is documented for c.1201C>T.
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.1201C>T in GALNT12 is a missense substitution predicted to produce NP_078918.3:p.(Arg401Cys). 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	Not assessed	Not assessed: no curated pathogenic or likely pathogenic alternate missense variant at GALNT12 Arg401 was available for comparison.	PMID:28944238
PM6	Not assessed	Not assessed: no affected individual with a presumed de novo c.1201C>T occurrence and incomplete parental confirmation is documented.
PP1	Not assessed	Not assessed: zero informative cosegregating affected relatives or meioses are documented for c.1201C>T.
PP2	Not assessed	Not assessed: two predicted-damaging GALNT12 missense variants were reported, but no validated gene-level missense mechanism or low benign-missense background was established.	PMID:28944238
PP3	Not met	Not met: REVEL 0.214 is below the >=0.644 supporting PP3 threshold.	revel
PP4	Not assessed	Not assessed: the exact variant was not documented with a highly specific phenotype, and colorectal cancer alone is insufficient phenotype specificity for PP4.	PMID:28944238 clinvar
PP5	Not met	Not met: ClinVar variation 410585 has zero expert-panel submissions and an overall Uncertain significance classification, not Pathogenic or Likely pathogenic.	clinvar
BA1	Not met	Not met: gnomAD v4.1 aggregate frequency is 1.79672e-05, far below the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest gnomAD v4.1 population frequency is 1.11393e-04, below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes but does not establish carrier health, disease penetrance, or the relevant GALNT12 disease model.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific functional assay or validated normal-function result was reported for GALNT12 p.Arg401Cys.
BS4	Not assessed	Not assessed: no informative unaffected variant-positive relatives or age-appropriate non-segregation analysis is documented.
BP1	Not assessed	Not assessed: loss-of-function context alone does not establish that GALNT12 disease is predominantly truncating with generally benign missense variation.	PMID:28944238
BP2	Not assessed	Not assessed: no cis pathogenic-variant or trans benign-variant co-occurrence with c.1201C>T is documented.
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.1201C>T in GALNT12 is a missense substitution predicted to produce NP_078918.3:p.(Arg401Cys). 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: REVEL 0.214 is below the <=0.29 BP4 threshold.	revel
BP5	Not assessed	Not assessed: no verified exact-variant case demonstrates an alternative molecular basis for the reported disease.	PMID:28944238 clinvar
BP6	Not met	Not met: ClinVar variation 410585 has zero expert-panel submissions and an overall Uncertain significance classification, not Benign or Likely benign.	clinvar
BP7	N/A	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.1201C>T in GALNT12 is a missense substitution predicted to produce NP_078918.3:p.(Arg401Cys). 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.	generic_acmg_combination_rules

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