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GALNT12
Final classification
VUS
GALNT12 c.-28C>T · p.?
GALNT12

NM_024642.5:c.-28C>T is a 5' UTR variant in GALNT12. It is present at extremely low frequency in gnomAD (v2.1 AF=0.00327%, v4.1 AF=0.00435%), meeting PM2 at supporting level.

Gene
GALNT12
Transcript
NM_024642.5
HGVS · transcript:coding
NM_024642.5:c.-28C>T
Consequence
N/A
GRCh38
chr9:98807671 C>T
GRCh37
chr9:101569953 C>T
Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2 VUS
GALNT12 c.-28C>T

NM_024642.5:c.-28C>T is a 5' UTR variant in GALNT12. It is present at extremely low frequency in gnomAD (v2.1 AF=0.00327%, v4.1 AF=0.00435%), meeting PM2 at supporting level.1 SpliceAI predicts no splicing impact (max delta score = 0.00), but this single line of computational evidence is insufficient to meet PP3 or BP4 thresholds. REVEL and BayesDel scores are unavailable as the variant does not alter an amino acid.2 This variant is absent from ClinVar and has not been reported in the published literature. No functional studies, case-control data, cosegregation data, or de novo observations are available.3 PVS1 is not applicable as c.-28C>T is a 5' UTR substitution rather than a null variant (nonsense, frameshift, canonical splice, initiation codon, or exon deletion) eligible under the ClinGen SVI framework.4 BS2 is not applicable for this gene: GALNT12 is a moderate-penetrance adult-onset cancer predisposition gene, and observation in healthy population controls does not constitute strong evidence against pathogenicity. The only criterion met is PM2 (supporting). All other assessed criteria are either not met, not assessed due to insufficient evidence, or not applicable. This yields a classification of Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 generic rules.5

PM2 VUS
Gene diagram · NM_024642.5 · variants mapped to exon structure
GALNT12 NM_024642.5
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 16 assessed
Applied · 1
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
NM_024642.5:c.-28C>T is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency = 0.00327% (1/30,612 alleles) and gnomAD v4.1 allele frequency = 0.00435% (48/1,104,678 alleles), both well below the 0.1% threshold for PM2 under generic ACMG/AMP rules. Zero homozygotes observed.
gnomAD v2.1 AF=3.27e-05 (1/306120 hom)gnomAD v4.1 AF=4.35e-05 (48/1104678
Assessed · not applied
Pathogenic
PS2 No de novo observation with confirmed maternity and paternity has been reported for NM_024642.5:c.-28C>T in ClinVar or the published literature.
PS3 No well-established functional studies demonstrating a damaging effect for NM_024642.5:c.-28C>T are available.
PS4 No case-control study comparing the prevalence of NM_024642.5:c.-28C>T in affected individuals versus controls has been published.
PM6 No de novo observation (without maternity/paternity confirmation) has been reported for NM_024642.5:c.-28C>T in ClinVar or the published literature.
PP1 No family cosegregation data are available for NM_024642.5:c.-28C>T.
PP3 Multiple lines of computational evidence do not support a deleterious effect.
PP4 No patient-specific phenotype or family history data were provided for assessment.
PP5 NM_024642.5:c.-28C>T is absent from ClinVar.
Benign
BA1 The allele frequency of NM_024642.5:c.-28C>T in gnomAD (v2.1: 0.00327%; v4.1: 0.00435%) is well below the 1% threshold for BA1 under generic ACMG/AMP rules.
BS1 The allele frequency of NM_024642.5:c.-28C>T in gnomAD (v2.1: 0.00327%; v4.1: 0.00435%) is well below the 0.3% threshold for BS1 under generic ACMG/AMP rules.
BS3 No well-established functional studies demonstrating no damaging effect for NM_024642.5:c.-28C>T are available.
BS4 No family segregation data demonstrating lack of cosegregation with disease are available for NM_024642.5:c.-28C>T.
BP2 No data are available on whether NM_024642.5:c.-28C>T has been observed in trans with a pathogenic variant in GALNT12 (relevant for a fully penetrant dominant disorder) or in cis with a pathogenic variant (relevant for a recessive disorder).
BP4 Multiple lines of computational evidence suggesting no impact are not available.
BP5 No data are available on whether NM_024642.5:c.-28C>T has been observed in a case with an alternate molecular basis for disease.
BP6 NM_024642.5:c.-28C>T is absent from ClinVar.
N/A · 11 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BS2 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 4.34516e-05; MAF= 0.00435%, 48/1104678 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.17253e-05; MAF= 0.00517%, 47/908646 alleles, homozygotes = 0); grpmax FAF= 3.985e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.26669e-05; MAF= 0.00327%, 1/30612 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.52146e-05; MAF= 0.00652%, 1/15334 alleles, homozygotes = 0).
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0043% · 48 / 1,104,678
0 hom · FAF 0.004%
European (non-Finnish)
47 / 908,646
0.0052%
Remaining individuals
1 / 36,278
0.0028%
+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0033% · 1 / 30,612
0 hom
European (non-Finnish)
1 / 15,334
0.0065%
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional No data
No calibrated functional assay or RNA evidence was identified for this variant.
OncoKB ↗
COSMIC screenshot
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
COSMIC ↗
Sources & reference links
6Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
SpliceAI
OncoKB
COSMIC