Classification rationale

VUS

GALNT12 c.460C>T missense · exon 2

No criterion was met: under the generic ACMG/AMP 2015 combination rules (no ClinGen VCEP exists for GALNT12), zero applied criteria yield a classification of VUS.

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

GALNT12 NM_024642.5

Fetching transcript structure from UCSC…

Applied criteria · 0 applied · 24 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 · 0

No criteria were applied for this variant.

Assessed · not applied · 5 not met · 19 not assessed

Pathogenic

PS1 Not assessed: no evidence of a different nucleotide change at this codon producing the identical p.Arg154Trp change with an established pathogenic classification.

PS2 Not assessed: no confirmed de novo occurrence of p.Arg154Trp is documented in the proband or family.

PS3 Not assessed: no functional assay data for this variant (e.g., glycosyltransferase activity) was available.

PS4 Not assessed: no case-control enrichment data, odds ratio, or significance was available for this variant.

PM1 Not assessed: no established germline mutational hotspot or critical domain map is defined for GALNT12.

PM2 Not met: the variant is present in gnomAD v4.1 (45/1,612,678 alleles, AF 2.8e-05), not absent from population databases.

PM3 Not assessed: no affected-proband observations or a pathogenic variant documented in trans with p.Arg154Trp were available.

PM5 Not assessed: no other missense change at Arg154 with an established pathogenic classification was available.

PM6 Not assessed: no suspected de novo occurrence of p.Arg154Trp without parental confirmation is documented.

PP1 Not assessed: no affected or unaffected relatives were tested, so cosegregation with disease cannot be evaluated.

PP2 Not assessed: no gene-level missense constraint metric (e.g., gnomAD missense Z-score) for GALNT12 was available.

PP3 Not met: REVEL score 0.607 falls in the gray zone [0.25-0.75], below the >0.75 PP3 threshold.

PP4 Not assessed: no patient-level phenotype documentation matching a GALNT12-associated disorder was available.

PP5 Not assessed: no ClinVar expert-panel pathogenic classification exists for this exact variant; all four submissions are uncertain significance.

Benign

BA1 Not met: highest observed population frequency is 8.0e-05 (gnomAD v4.1 African/African American), far below the >5% BA1 threshold.

BS1 Not met: maximum observed allele frequency is 2.8e-05 (gnomAD v4.1), not higher than expected for a rare Mendelian disease allele.

BS2 Not assessed: no homozygous carriers or healthy adult genotype observations were reported.

BS3 Not assessed: no functional assay data showing wild-type-like activity for this variant was available.

BS4 Not assessed: no informative affected relatives lacking the variant were documented.

BP1 Not assessed: no gene-specific evidence establishes that missense changes are not a recognized disease mechanism in GALNT12.

BP2 Not assessed: no co-occurrence of this variant with a pathogenic variant (in trans or cis) was documented.

BP4 Not met: REVEL score 0.607 is above the <0.25 BP4 threshold.

BP5 Not assessed: no alternative molecular diagnosis explaining the patient's presentation was documented.

BP6 Not assessed: no ClinVar expert-panel benign classification exists for this exact variant.

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= 2.79039e-05; MAF= 0.00279%, 45/1612678 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 7.99574e-05; MAF= 0.00800%, 6/75040 alleles, homozygotes = 0); grpmax FAF= 3.467e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.98815e-05; MAF= 0.00199%, 5/251490 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000123031; MAF= 0.01230%, 2/16256 alleles, homozygotes = 0); grpmax FAF= 2.132e-05.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0001085894233901618, 2/18418 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0028% · 45 / 1,612,678
0 hom · FAF 0.0035%

African/African American 6 / 75,040	0.008%
Admixed American 2 / 60,030	0.0033%
European (non-Finnish) 35 / 1,178,604	0.003%
South Asian 2 / 91,042	0.0022%

+ 6 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.002% · 5 / 251,490
0 hom · FAF 0.0021%

African/African American 2 / 16,256	0.012%
South Asian 1 / 30,616	0.0033%
European (non-Finnish) 2 / 113,766	0.0018%

+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)

gnomAD Canada 🇨🇦

0.011% · 2 / 18,418
0 hom · FAF 0.003%

European (non-Finnish)

2 / 11,742

0.017%

+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories). (ClinVarID = 241514)

ClinVar ↗

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.31). REVEL score = 0.607. BayesDel score = 0.252221.

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; COSV66663279, n = 3 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

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

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