Variant classification summary

NM_080605.4:c.901_904dup

B3GALT6 · NP_542172.2:p.(Arg302GlnfsTer142) · NM_080605.4

GRCh37: chr1:1168556 T>TGCAA · GRCh38: chr1:1233176 T>TGCAA

Gene: B3GALT6 Transcript: NM_080605.4

Final call

VUS

PVS1 strong PM2 supporting

Variant details

Gene

B3GALT6

Transcript

NM_080605.4

Protein

NP_542172.2:p.(Arg302GlnfsTer142)

gnomAD AF

9.061500403236768e-06 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_080605.4:c.901_904dup is a frameshift variant in B3GALT6 predicted to alter the C-terminus (p.Arg302GlnfsTer142). B3GALT6 loss of function is a well-established disease mechanism for autosomal recessive spondylodysplastic Ehlers-Danlos syndrome. PVS1 is applied at strong strength, downgraded from very_strong due to the 3' location (codon 302/330) and confirmed NMD escape in this single-exon gene (PMC6185798).

2

The variant is extremely rare in population databases, meeting PM2_Supporting: gnomAD v2.1 allele frequency 7.17e-06 (1/139,512 alleles) and gnomAD v4.1 allele frequency 9.06e-06 (14/1,544,998 alleles), both well below the 0.1% threshold. No homozygotes are observed.

3

The variant is present in ClinVar (Variation ID 1323966) with four clinical testing submissions: two classify it as Likely Pathogenic and two as Uncertain Significance. No expert panel review is available, and the cited PubMed references (PMID:25741868, PMID:28492532) are methodology guidelines that do not specifically mention this variant.

4

SpliceAI predicts no significant splicing impact (max delta score 0.03). In silico missense predictors (REVEL, BayesDel) are not applicable to this frameshift variant. PP3 is not met; BP4 is not met given insufficient benign computational evidence.

5

Applying generic ACMG/AMP 2015 final classification rules (PMID:25741868): with one strong pathogenic criterion (PVS1_Strong) and one supporting pathogenic criterion (PM2_Supporting), the variant does not reach the threshold for Likely Pathogenic (requires 1 Strong + 1–2 Moderate OR 1 Strong + 2 Supporting). The variant is classified as a Variant of Uncertain Significance (VUS). Additional evidence, particularly verified publication reports of the variant in affected individuals (PS4/PM3) and segregation data (PP1), may upgrade the classification upon human curator review.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of 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	Met	This duplication (c.901_904dup) is a frameshift variant predicted to result in a premature termination codon (p.Arg302GlnfsTer142). B3GALT6 loss of function is a well-established disease mechanism for autosomal recessive spondylodysplastic Ehlers-Danlos syndrome (spEDS-B3GALT6). However, NM_080605.4 is a single-exon transcript and the frameshift occurs at codon 302 of 330, near the 3' end; NMD is not expected to be triggered. Per the ClinGen SVI PVS1 framework (PMC6185798), PVS1 is downgraded from very_strong to strong due to confirmed NMD escape in a 3' region.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies when the variant produces the same amino acid change as a previously established pathogenic variant. This is a frameshift duplication, not a nucleotide substitution, and does not share an amino acid change with any established pathogenic single-nucleotide variant.
PS2	Not met	No de novo occurrence of NM_080605.4:c.901_904dup has been reported with confirmed maternity and paternity. B3GALT6-related disorders are autosomal recessive; a single de novo heterozygous event would not be causative under standard ACMG/AMP interpretation for recessive disease, making PS2 effectively inapplicable regardless.
PS3	Not assessed	No functional studies evaluating the impact of NM_080605.4:c.901_904dup on B3GALT6 protein function were identified. REVEL and BayesDel are not applicable (variant is a duplication, not an SNV). No variant-specific functional data available in ClinVar submissions or the literature reviewed.
PS4	Not assessed	The variant prevalence in affected individuals versus the general population could not be reliably established. The variant is present at extremely low frequency in gnomAD (v2.1 AF=7.17e-06; v4.1 AF=9.06e-06), but no verified publication reports the variant in multiple affected probands with adequate case-control statistics. Exploratory claims referencing Malfait et al. (PMID:23664117) could not be verified against available full-text or abstract resources.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 applies when a different nucleotide change at the same amino acid position has been established as pathogenic. This is a frameshift duplication that alters the reading frame starting at codon 302; no single-nucleotide change at the same position producing the identical altered reading frame has been reported.
PM1	Not assessed	No established mutational hotspot or critical functional domain data specific to B3GALT6 residue 302 or the C-terminal region are available to support PM1. The variant does not lie in a statistically significant cancer hotspot (per hotspots screen).
PM2	Met	This variant is present at extremely low frequency in population databases: gnomAD v2.1 allele frequency 7.17e-06 (1/139,512 alleles, 0.00072%) and gnomAD v4.1 allele frequency 9.06e-06 (14/1,544,998 alleles, 0.00091%). Both are well below the 0.1% PM2 threshold. No homozygotes are reported. Absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4
PM4	N/A	PM4 applies to protein length changes from in-frame deletions/insertions in non-repeat regions or stop-loss variants. The c.901_904dup is a 4-bp duplication that causes a frameshift (p.Arg302GlnfsTer142), not an in-frame change. Frameshift variants are assessed under PVS1, not PM4.
PM5	N/A	PM5 requires a different missense change at the same residue that has been established as pathogenic. This is a frameshift variant, not a missense change, and no same-residue missense comparator candidates were identified (per pm5_candidates.json).
PM6	Not met	No report of a de novo occurrence of NM_080605.4:c.901_904dup exists in the literature or ClinVar submissions, even without confirmed maternity/paternity. PM6 requires a de novo observation, which is absent for this variant.
PP1	Not assessed	Cosegregation evidence could not be independently verified. Exploratory claims describe an affected sibling pair in Malfait et al. (PMID:23664117) carrying c.901_904dup in trans with c.194dup, but the full text for this PMID was not available and the abstract for the companion paper (PMID:23664118) does not mention c.901_904dup. Without verifiable segregation data, PP1 cannot be applied.
PP2	N/A	PP2 applies to missense variants in genes where missense variants are a predominant disease mechanism and benign missense variation is low. This variant is a frameshift, not a missense change.
PP3	Not met	SpliceAI predicts no significant splice impact (max delta score = 0.03). REVEL and BayesDel in silico scores are not available for this variant (non-SNV). HCI prior is not supported for B3GALT6. Multiple lines of computational evidence supporting a deleterious effect are absent.	spliceai
PP4	Not assessed	PP4 requires the patient's phenotype or family history to be highly specific for the disease with a single genetic etiology. No patient phenotype data was included in the case files for assessment.
PP5	N/A	PP5 requires a reputable source to have classified the variant as pathogenic without independent verification. ClinVar submissions are split (2 Likely Pathogenic, 2 Uncertain Significance) with no expert panel review. No single authoritative source has asserted pathogenicity for this variant.	clinvar
BA1	Not met	The highest population allele frequency is 0.00194% in the Admixed American population (gnomAD v4.1) and 0.00189% in European non-Finnish (gnomAD v2.1). Both are well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The highest population allele frequency is 0.00194% (gnomAD v4.1, AMR population). This is well below the 0.3% BS1 threshold. The variant is too rare in the general population to support a benign interpretation.	gnomad_v2 gnomad_v4
BS2	Not assessed	BS2 requires observation of the variant in a healthy adult homozygous state or in trans with a pathogenic variant for a fully penetrant dominant disorder. No homozygous occurrences are reported in gnomAD. No verified data on healthy homozygous carriers exists. For recessive disorders, observation in trans with a pathogenic variant is expected in affected individuals and does not support BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No functional studies demonstrating no deleterious effect of NM_080605.4:c.901_904dup were identified. REVEL and BayesDel are not applicable (non-SNV). No well-established functional assay data exist for this variant showing normal protein function.
BS4	Not met	No evidence of non-segregation with disease has been reported. BS4 requires the variant to fail to segregate with disease in affected family members; available data may suggest segregation (though unverified) but does not support non-segregation.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism. This variant is a frameshift, not a missense change.
BP2	Not met	BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant. No such observations have been reported. For B3GALT6-related recessive disease, observation in trans with another pathogenic variant supports pathogenicity (PM3) rather than BP2.
BP3	N/A	BP3 applies to in-frame deletions or insertions in repetitive regions without a known function. This variant is a frameshift duplication, not an in-frame change in a repetitive region.
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. SpliceAI predicts no significant splicing impact (max delta 0.03), but this alone is insufficient as 'multiple lines.' REVEL and BayesDel are not applicable. There is insufficient benign computational evidence to meet BP4.	spliceai
BP5	Not assessed	BP5 requires an alternative molecular basis for disease to be identified in the case. No case-level data on alternative molecular diagnoses was provided in the case files.
BP6	Not assessed	BP6 requires a reputable source to classify the variant as benign without independent verification. ClinVar submissions for this variant are split between Likely Pathogenic and Uncertain Significance; no submitter has classified this as Benign or Likely Benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant is a frameshift duplication, not a synonymous change.

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