NM_024642.5:c.5G>A

GALNT12 · NP_078918.3:p.(Trp2Ter) · NM_024642.5

GRCh37: chr9:101569985 G>A · GRCh38: chr9:98807703 G>A

Gene: GALNT12 Transcript: NM_024642.5

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

GALNT12

Transcript

NM_024642.5

Protein

NP_078918.3:p.(Trp2Ter)

gnomAD AF

5.2066610550430855e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

PVS1 (very_strong) met: NM_024642.5:c.5G>A is a nonsense variant (p.Trp2Ter) in exon 1 of the MANE Select transcript of GALNT12, a gene with an established loss-of-function mechanism for germline cancer predisposition. The premature stop at codon 2 is predicted to trigger nonsense-mediated decay.

PM2 (moderate) met: This variant is present at extremely low frequency in population databases (gnomAD v2.1 AF=0.00341%, v4.1 AF=0.00052%), well below the 0.1% threshold. No homozygotes observed in gnomAD.

The combination of PVS1 (very strong) and PM2 (moderate) results in a classification of Likely Pathogenic per generic ACMG/AMP 2015 criteria (Richards et al. 2015, PMID:25741868).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	Nonsense variant NM_024642.5:c.5G>A (p.Trp2Ter) in exon 1 of 10, the MANE Select transcript of GALNT12, a gene with an established loss-of-function mechanism for germline cancer predisposition. The premature termination codon at amino acid position 2 is predicted to trigger nonsense-mediated decay, resulting in absence of functional protein. No evidence of alternative start codon rescue or non-critical exon involvement.	pvs1_generic_framework gnomad_v2 gnomad_v4 pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to missense variants where a different nucleotide change produces the same amino acid substitution previously established as pathogenic. Not applicable to nonsense variants.
PS2	Not met	No de novo occurrence with confirmed maternity and paternity was identified for this variant in any reviewed source.
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrating a damaging effect specific to NM_024642.5:c.5G>A were identified in the reviewed literature.
PS4	Not met	The variant has been observed in one homozygous case (26-year-old female with grade 1 endometrioid endometrial carcinoma, PMID:30886832) and reported in one gastric adenocarcinoma case (PMID:32963463, per ClinVar submission SCV002655098). The prevalence in affected individuals does not reach statistical significance over general population frequency required for PS4.	PMID:30886832 gnomad_v2 gnomad_v4
PS5	N/A	PS5 applies when a different nucleotide change at the same codon has been established as pathogenic; not applicable to nonsense variants at this codon as no alternative pathogenic missense has been established at codon 2.
PM1	Not met	Variant does not lie within a statistically significant mutational hotspot (cancerhotspots.org negative), and no well-established critical or well-characterized functional domain has been defined at amino acid position 2 of GALNT12.
PM2	Met	The variant is present at extremely low frequency in population databases: gnomAD v2.1 overall AF=0.00341% (1/29,340 alleles, 0 homozygotes), maximum subpopulation AF=0.01178% (African/African American); gnomAD v4.1 overall AF=0.00052% (6/1,152,370 alleles, 0 homozygotes), maximum subpopulation AF=0.00658% (African/African American). All observed frequencies are well below the 0.1% PM2 threshold. Absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator pathogenic missense variants were identified in ClinVar. PM5 candidates pipeline returned 0 candidates at codon 2; PM5 cannot be applied.	pm5_candidates
PM6	Not met	No de novo observation (without confirmation of maternity and paternity) was identified for this variant in any reviewed source.
PP1	Not met	No cosegregation data with disease in multiple affected family members are available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense is a common mechanism of disease. This is a nonsense variant.
PP3	Not met	SpliceAI predicts no splicing impact (max delta score = 0.00). BayesDel score of 0.22007 is below commonly used pathogenic thresholds. REVEL score not available. In silico tools do not provide pathogenic support for this nonsense variant, and for premature termination variants, computational splicing predictors are not the primary pathogenic mechanism under assessment.	spliceai bayesdel
PP4	Not met	Although the variant has been observed in a 26-year-old homozygous patient with grade 1 endometrioid endometrial carcinoma (PMID:30886832) and in a gastric adenocarcinoma patient (PMID:32963463), these cancer phenotypes are not highly specific for GALNT12-related disease. GALNT12 is a moderate-penetrance cancer predisposition gene, and endometrial and gastric cancers have heterogeneous genetic etiologies.	PMID:30886832 PMID:32963463
PP5	Not met	The variant is classified as Uncertain Significance in ClinVar (VariationID: 1061178) by two clinical laboratories (Ambry Genetics, Labcorp/Invitae). No reputable source has reported this variant as definitively pathogenic.	clinvar
BA1	Not met	The maximum population allele frequency is 0.01178% (African/African American, gnomAD v2.1), well below the 1% BA1 threshold. Does not meet stand-alone benign criterion.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum population allele frequency is 0.01178% (African/African American, gnomAD v2.1), well below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No homozygous healthy adult carriers have been observed in population databases (gnomAD v2.1: 0 homozygotes; gnomAD v4.1: 0 homozygotes). The single homozygous observation was in a 26-year-old with endometrial carcinoma (PMID:30886832), not a healthy control.	gnomad_v2 gnomad_v4 PMID:30886832
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing were identified for this variant.
BS4	Not met	No segregation data in affected families are available for this variant; BS4 requires lack of segregation in multiple affected family members.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is a truncating (nonsense) variant.
BP2	Not met	No evidence of this variant observed in trans with a known pathogenic variant in GALNT12. Observation in trans with a dominant pathogenic variant would support benign classification, but no such data exist.
BP4	Not met	While SpliceAI predicts no splice impact (max delta score = 0.00), BP4 requires multiple lines of computational evidence suggesting no impact on gene product. For this nonsense variant, the primary pathogenic mechanism is protein truncation rather than splicing, and SpliceAI alone does not constitute multiple lines of benign evidence. BayesDel score of 0.22007 is not in the clearly benign range.	spliceai bayesdel
BP5	Not met	No cases have been identified where an alternate molecular basis for disease was found in an individual carrying this variant.
BP6	Not met	No reputable source has classified this variant as benign or likely benign. ClinVar classification is Uncertain Significance (VariationID: 1061178).	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. This is a nonsense variant.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.