NM_080605.4:c.902_905dup

B3GALT6 · NP_542172.2:p.(Glu303AlafsTer141) · NM_080605.4

GRCh37: chr1:1168559 A>AAGCG · GRCh38: chr1:1233179 A>AAGCG

Gene: B3GALT6 Transcript: NM_080605.4

Final call

VUS

PVS1 moderate PM2 moderate

Variant details

Gene

B3GALT6

Transcript

NM_080605.4

Protein

NP_542172.2:p.(Glu303AlafsTer141)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_080605.4:c.902_905dup is a 4bp duplication producing a frameshift predicted to yield NP_542172.2:p.(Glu303AlafsTer141) in B3GALT6, a gene where loss of function is an established disease mechanism for autosomal recessive Ehlers-Danlos-syndrome-like connective tissue disorder (PVS1_Moderate; PMID:23664118, PMC6185798). The NM_080605.4 transcript is MANE Select and represents the single exon of B3GALT6; nonsense-mediated decay is not expected, warranting a downgrade from PVS1_VeryStrong to PVS1_Moderate per ClinGen SVI PVS1 recommendations.

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases (allele frequency = 0.0 in all datasets), meeting PM2 for extremely low population frequency.

Combining the above, two moderate-level pathogenic criteria (PVS1_Moderate + PM2_Moderate) are insufficient to reach a Likely Pathogenic classification under generic ACMG/AMP 2015 combination rules (PMID:25741868), which require at minimum one Very Strong plus one Moderate, one Strong plus one Moderate, or three Moderate criteria. No benign criteria are met. The variant is classified as a Variant of Uncertain Significance (VUS).

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	NM_080605.4:c.902_905dup is a 4bp duplication producing a frameshift that predicts NP_542172.2:p.(Glu303AlafsTer141). B3GALT6 loss of function is an established disease mechanism for autosomal recessive Ehlers-Danlos-syndrome-like connective tissue disorder (PMID:23664118). The NM_080605.4 transcript is MANE Select and constitutes the single exon of B3GALT6; nonsense-mediated decay is not expected. Under ClinGen SVI PVS1 recommendations (PMC6185798), frameshift variants in single-exon genes where NMD cannot occur warrant a downgrade from Very Strong to Moderate.	pvs1_generic_framework
PS1	N/A	PS1 applies to same amino acid changes arising from different nucleotide substitutions; not applicable to a 4bp duplication producing a frameshift.
PS2	Not assessed	No de novo data with confirmed paternity and maternity available for this variant.
PS3	Not assessed	No well-established in vitro or in vivo functional studies specific to NM_080605.4:c.902_905dup are available.
PS4	Not assessed	No case-control data demonstrating statistically increased prevalence of this variant in affected individuals versus controls is available.
PS5	Not assessed	No data on this variant observed in trans with a known pathogenic variant in B3GALT6 is available.
PM1	Not assessed	No data demonstrating that this variant lies within a well-established mutational hotspot or critical functional domain with supporting statistical evidence is available.
PM2	Met	NM_080605.4:c.902_905dup is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases (allele frequency = 0.0 in all datasets), meeting PM2 for extremely low/absent population frequency.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 skipped per explicit instruction — criterion marked as trivially not_applicable.
PM4	N/A	PM4 applies to in-frame deletions/insertions and stop-loss variants. NM_080605.4:c.902_905dup is a frameshift duplication, not an in-frame change.
PM5	N/A	PM5 applies to novel missense changes at residues where a different pathogenic missense substitution has been established. This is a frameshift variant; PM5 candidate search confirmed no eligible same-residue missense comparators exist (pm5_candidates.json).
PM6	Not assessed	No assumed de novo observation (without parental confirmation) is available for this variant.
PP1	Not assessed	No cosegregation data in multiple affected family members is available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. NM_080605.4:c.902_905dup is a frameshift variant.
PP3	Not met	SpliceAI predicts no significant splice impact (max delta score = 0.02). REVEL, BayesDel, and HCI Prior scores are unavailable for this duplication variant. No computational evidence supports a deleterious effect at the nucleotide or splicing level.	spliceai
PP4	Not assessed	No patient phenotype or family history data specific to this variant is available.
PP5	Not assessed	This variant is absent from ClinVar; no reputable source has reported it as pathogenic.
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0.0), far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from all population databases (AF = 0.0), failing to meet the BS1 threshold of >0.3% allele frequency.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data on observation of this variant in healthy adult individuals for a fully penetrant disorder is available.
BS3	Not assessed	No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this specific variant are available.
BS4	Not assessed	No segregation data demonstrating lack of cosegregation with disease in affected family members is available.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. NM_080605.4:c.902_905dup is itself a truncating (frameshift) variant.
BP2	Not assessed	No data on observation of this variant in trans with a pathogenic variant (for a dominant disorder) or in cis with a pathogenic variant (any inheritance pattern) is available.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. NM_080605.4:c.902_905dup is a frameshift variant.
BP4	Not met	Multiple lines of computational evidence do not support a benign effect. SpliceAI shows no significant splice impact (max delta = 0.02), but this finding does not constitute benign evidence for a frameshift variant whose pathogenic mechanism operates at the protein level. REVEL, BayesDel, and HCI Prior are not applicable to duplication variants.	spliceai
BP5	Not assessed	No data on an alternate molecular basis for disease in a case carrying this variant is available.
BP6	Not assessed	This variant is absent from ClinVar; no reputable source has reported it as benign.
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_080605.4:c.902_905dup is a frameshift duplication.

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.