Classification rationale

PM2 BP7 VUS

GALNT12 c.123T>G

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

PM2 + BP7 → VUS

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

GALNT12 NM_024642.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 17 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (supporting): gnomAD v4.1 total allele frequency is 0.0001% (1/1,042,398 alleles), far below the 0.1% threshold.

gnomad_v4: total AF 9.59326e-07 (0.0001%), 1/1,042,398 alleles, 0 homozygotes; AMR AF 5.72e-05 (0.0057%)gnomad_v2: total AF 4.03942e-05 (0.004%), 1/24,756 alleles, 0 homozygotesLab non-VCEP PM2 threshold: AF <0.1% in gnomAD (generic ACMG fallback framework, PMID 25741868)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP7 supporting review Benign

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.

pvs1_variant_assessment: variant class 'synonymous' (NP_078918.3:p.(Arg41=)); canonical_splice_consensus false -> variant is a synonymous change outside the canonical splice consensus, satisfying the variant-type prong of BP7.SpliceAI (Jaganathan et al. 2019, PMID 30661751): max delta score = 0.00; DS_AG=0.0 (no acceptor gain), DS_AL=0.0 (no acceptor loss), DS_DG=0.0 (no donor gain), DS_DL=0.0 (no donor loss); below the >=0.2 splice-impact threshold of the SpliceAI publication (PMID 30661751) -> no predicted impact on splice consensus and no predicted creation of new splice sites.Generic ACMG/AMP 2015 BP7 definition (Richards et al. 2015, PMID 25741868) applied because no ClinGen CSPEC/VCEP exists for GALNT12.

spliceai ↗

Assessed · not applied

Pathogenic

PS2 Not assessed: no proband genotype or parental testing data were available to evaluate a confirmed de novo occurrence.

PS3 Not assessed: no functional assay evidence for this variant was available to evaluate a damaging effect.

PS4 Not assessed: no case-control or cohort data for this variant were available to evaluate enrichment in affected individuals.

PM3 Not met: no pathogenic variant in trans is documented, and no recessive inheritance framework applies to this variant.

PM6 Not assessed: no proband-parent trio data or de novo observation of this variant were available.

PP1 Not assessed: no affected family members were tested, so no segregation data were available.

PP3 Not met: SpliceAI max delta 0.00 shows no predicted splice impact, far below the 0.2 threshold.

PP4 Not assessed: no phenotype or family-history data were available for carriers of this variant.

PP5 Not met: no ClinVar expert-panel classification of pathogenic exists for this variant; only ordinary laboratory submissions.

Benign

BA1 Not met: highest population allele frequency is 0.000096% (gnomAD v4.1), far below the 1% benign threshold.

BS1 Not met: highest robust population frequency is 0.0057% (AMR), below the 0.3% threshold.

BS3 Not assessed: no functional studies demonstrating absence of a damaging effect were available.

BS4 Not assessed: no affected family members were tested, so lack of segregation could not be evaluated.

BP2 Not met: no second pathogenic variant or phase data show this variant in cis or trans with a pathogenic allele.

BP4 Not met: the only computational prediction (SpliceAI max delta 0.00) is counted under BP7, leaving no independent line of evidence.

BP5 Not assessed: no proband case data were available to evaluate an alternative molecular basis for disease.

BP6 Not met: no ClinVar expert-panel benign classification exists; the 'Likely benign' label comes from ordinary laboratory submissions.

N/A · 9 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BS2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 9.59326e-07; MAF= 0.00010%, 1/1042398 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.72148e-05; MAF= 0.00572%, 1/17478 alleles, homozygotes = 0).

v2.1

This variant is present in gnomAD v2.1 (AF= 4.03942e-05; MAF= 0.00404%, 1/24756 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.0026738; MAF= 0.26738%, 1/374 alleles, homozygotes = 0).

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

9.6e-05% · 1 / 1,042,398
0 hom

Admixed American

1 / 17,478

0.0057%

+ 9 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

0.004% · 1 / 24,756
0 hom

Admixed American

1 / 374

0.27%

+ 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

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 Likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 1758097)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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 not previously been reported in somatic cancers (COSMIC).

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