Variant classification summary

NM_024642.5:c.460C>T

GALNT12 · NP_078918.3:p.(Arg154Trp) · NM_024642.5

GRCh37: chr9:101585626 C>T · GRCh38: chr9:98823344 C>T

Gene: GALNT12 Transcript: NM_024642.5

Final call

VUS

Variant details

Gene

GALNT12

Transcript

NM_024642.5

Protein

NP_078918.3:p.(Arg154Trp)

gnomAD AF

2.7903896500107274e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

Final determination: Generic ACMG/AMP 2015 fallback: with no criteria applied in either direction, no Pathogenic/Likely Pathogenic/Benign/Likely Benign combination threshold is met, so the variant defaults to Uncertain Significance.

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	N/A	Not applicable: this is a missense change (p.Arg154Trp), not a null variant, so no nonsense-mediated decay or truncation mechanism applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	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	Not assessed: no confirmed de novo occurrence of p.Arg154Trp is documented in the proband or family.
PS3	Not assessed	Not assessed: no functional assay data for this variant (e.g., glycosyltransferase activity) was available.
PS4	Not assessed	Not assessed: no case-control enrichment data, odds ratio, or significance was available for this variant.
PM1	Not assessed	Not assessed: no established germline mutational hotspot or critical domain map is defined for GALNT12.
PM2	Not met	Not met: the variant is present in gnomAD v4.1 (45/1,612,678 alleles, AF 2.8e-05), not absent from population databases.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no affected-proband observations or a pathogenic variant documented in trans with p.Arg154Trp were available.	PMID:25741868
PM4	N/A	Not applicable: this is a missense change, so no alteration in protein length occurs.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no other missense change at Arg154 with an established pathogenic classification was available.
PM6	Not assessed	Not assessed: no suspected de novo occurrence of p.Arg154Trp without parental confirmation is documented.
PP1	Not assessed	Not assessed: no affected or unaffected relatives were tested, so cosegregation with disease cannot be evaluated.
PP2	Not assessed	Not assessed: no gene-level missense constraint metric (e.g., gnomAD missense Z-score) for GALNT12 was available.
PP3	Not met	Not met: REVEL score 0.607 falls in the gray zone [0.25-0.75], below the >0.75 PP3 threshold.	revel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no patient-level phenotype documentation matching a GALNT12-associated disorder was available.	clinvar
PP5	Not assessed	Not assessed: no ClinVar expert-panel pathogenic classification exists for this exact variant; all four submissions are uncertain significance.	clinvar
BA1	Not met	Not met: highest observed population frequency is 8.0e-05 (gnomAD v4.1 African/African American), far below the >5% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: maximum observed allele frequency is 2.8e-05 (gnomAD v4.1), not higher than expected for a rare Mendelian disease allele.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not assessed	Not assessed: no homozygous carriers or healthy adult genotype observations were reported.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay data showing wild-type-like activity for this variant was available.
BS4	Not assessed	Not assessed: no informative affected relatives lacking the variant were documented.
BP1	Not assessed	Not assessed: no gene-specific evidence establishes that missense changes are not a recognized disease mechanism in GALNT12.
BP2	Not assessed	Not assessed: no co-occurrence of this variant with a pathogenic variant (in trans or cis) was documented.	PMID:25741868
BP3	N/A	Not applicable: this is a missense change, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL score 0.607 is above the <0.25 BP4 threshold.	revel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no alternative molecular diagnosis explaining the patient's presentation was documented.
BP6	Not assessed	Not assessed: no ClinVar expert-panel benign classification exists for this exact variant.	clinvar
BP7	N/A	Not applicable: this is a missense change, not a synonymous variant.	generic_acmg_combination_rules

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.