Classification rationale

BP4 VUS

GALNT12 c.1201C>T missense · exon 6

BP4 supporting: REVEL 0.214 is below the <=0.29 missense threshold. VUS: BP4 alone does not meet the generic ACMG/AMP threshold for Likely Benign or Benign.

BP4 → VUS

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.

Gene diagram · NM_024642.5 · variants mapped to exon structure

GALNT12 NM_024642.5

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 23 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

Met at supporting strength: REVEL 0.214 is below the <=0.29 BP4 threshold.

The normalized consequence is missense, NP_078918.3:p.(Arg401Cys), so REVEL is the sole applicable PP3/BP4 predictor path.The case-specific REVEL score is 0.214; the supplied generic ClinGen SVI calibration assigns supporting BP4 at <=0.29.The supplied REVEL thresholds are from the ClinGen SVI calibration of Pejaver et al. 2022, PMID:36413997.

Assessed · not applied · 8 not met · 15 not assessed

Pathogenic

PS1 Not met: no independently reported pathogenic or likely pathogenic variant producing the same GALNT12 p.Arg401Cys amino-acid change was identified.

PS2 Not assessed: no documented de novo observation with confirmed maternity and paternity is available for c.1201C>T.

PS3 Not assessed: no variant-specific functional assay or validated damaging-effect result was reported for GALNT12 p.Arg401Cys.

PS4 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.

PM1 Not met: residue 401 is not reported in a statistically significant hotspot, and no approved GALNT12 critical-domain table is available.

PM2 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.

PM3 Not assessed: no affected-proband, phase, or pathogenic-in-trans observation is documented for c.1201C>T.

PM5 Not assessed: no curated pathogenic or likely pathogenic alternate missense variant at GALNT12 Arg401 was available for comparison.

PM6 Not assessed: no affected individual with a presumed de novo c.1201C>T occurrence and incomplete parental confirmation is documented.

PP1 Not assessed: zero informative cosegregating affected relatives or meioses are documented for c.1201C>T.

PP2 Not assessed: two predicted-damaging GALNT12 missense variants were reported, but no validated gene-level missense mechanism or low benign-missense background was established.

PP3 Not met: REVEL 0.214 is below the >=0.644 supporting PP3 threshold.

PP4 Not assessed: the exact variant was not documented with a highly specific phenotype, and colorectal cancer alone is insufficient phenotype specificity for PP4.

PP5 Not met: ClinVar variation 410585 has zero expert-panel submissions and an overall Uncertain significance classification, not Pathogenic or Likely pathogenic.

Benign

BA1 Not met: gnomAD v4.1 aggregate frequency is 1.79672e-05, far below the 0.05 BA1 threshold.

BS1 Not met: the highest gnomAD v4.1 population frequency is 1.11393e-04, below the generic BS1 threshold of 0.01.

BS2 Not assessed: gnomAD reports zero homozygotes but does not establish carrier health, disease penetrance, or the relevant GALNT12 disease model.

BS3 Not assessed: no variant-specific functional assay or validated normal-function result was reported for GALNT12 p.Arg401Cys.

BS4 Not assessed: no informative unaffected variant-positive relatives or age-appropriate non-segregation analysis is documented.

BP1 Not assessed: loss-of-function context alone does not establish that GALNT12 disease is predominantly truncating with generally benign missense variation.

BP2 Not assessed: no cis pathogenic-variant or trans benign-variant co-occurrence with c.1201C>T is documented.

BP5 Not assessed: no verified exact-variant case demonstrates an alternative molecular basis for the reported disease.

BP6 Not met: ClinVar variation 410585 has zero expert-panel submissions and an overall Uncertain significance classification, not Benign or Likely benign.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.79672e-05; MAF= 0.00180%, 29/1614052 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000111393; MAF= 0.01114%, 5/44886 alleles, homozygotes = 0); grpmax FAF= 4.345e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.19432e-05; MAF= 0.00119%, 3/251188 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000108731; MAF= 0.01087%, 2/18394 alleles, homozygotes = 0); grpmax FAF= 1.897e-05.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0018% · 29 / 1,614,052
0 hom · FAF 0.0043%

East Asian 5 / 44,886	0.011%
Remaining individuals 3 / 62,482	0.0048%
South Asian 2 / 91,084	0.0022%
European (non-Finnish) 18 / 1,180,042	0.0015%
African/African American 1 / 74,918	0.0013%

+ 5 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.0012% · 3 / 251,188
0 hom · FAF 0.0019%

East Asian 2 / 18,394	0.011%
South Asian 1 / 30,616	0.0033%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 410585)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.214. BayesDel score = -0.250434.

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66662243, n = 6 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 2 PMIDs not cited in assessment

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

28944238 ↗ Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes. CLINVAR

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