B3GALT6c.901_904dupUncertain significance

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Variant interpretation report

B3GALT6 c.901_904dup, p.(Arg302GlnfsTer142)

NM_080605.4:c.901_904dup NP_542172.2:p.(Arg302GlnfsTer142) View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About B3GALT6

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 strong (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 8 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PVS1 (strong): 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.
PM2 (supporting): 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.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PVS1Strong

PVS1 · strong

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.

PM2Supporting

PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 strong, PM2 supporting; combination = 1 strong + 1 supporting, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

14 / 1,544,998 alleles

gnomAD v4.1: 14 / 1,544,998 alleles. Recorded AF 9.0615e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 7.16784e-06; MAF= 0.00072%, 1/139512 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.89415e-05; MAF= 0.00189%, 1/52794 alleles, homozygotes = 0).

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.030 maximum delta

Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 8 not met · 9 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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).

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.

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.

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.

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.

Met · 2

PVS1 StrongThis 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. Details ▾Hide ▴

Evidence considered

Frameshift variant c.901_904dup leading to p.Arg302GlnfsTer142
B3GALT6 LoF is an established disease mechanism for spEDS-B3GALT6 (supported by PMID:23664118
PMID:25331875
PMID:38065100)
Single-exon gene
NMD escape predicted
variant in 3' region (codon 302/330)
ClinGen SVI PVS1 downgrade framework (PMC6185798) applied

Still missing

No direct biochemical confirmation of protein absence or functional consequence of the altered C-terminus

Sources

pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment236641182533187538065100

PM2 SupportingThis 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=7.17e-06 (1/139
512
0 homozygotes)
gnomAD v4.1: AF=9.06e-06 (14/1
544
998
gnomAD-Canada: absent
Highest subpopulation AF: NFE 0.00189% (v2.1)
AMR 0.00194% (v4.1)

Sources

gnomad_v2 ↗gnomad_v4 ↗

Not met · 8 · evaluated, threshold not reached

PS2 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. Details ▾Hide ▴

Evidence considered

B3GALT6-associated disease is autosomal recessive
No published de novo reports of c.901_904dup

PM6 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. Details ▾Hide ▴

Evidence considered

No de novo reports in ClinVar or literature

PP3 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. Details ▾Hide ▴

Evidence considered

SpliceAI: max delta = 0.03 (no significant splice impact)
REVEL: not applicable (non-SNV)
BayesDel: not applicable (non-SNV)
HCI prior: gene not supported

Sources

spliceai ↗

BA1 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 max subpopulation AF: 0.00189% (NFE)
gnomAD v4.1 max subpopulation AF: 0.00194% (AMR)
Both far below BA1 threshold of 1%

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 overall AF: 0.00072%
gnomAD v4.1 overall AF: 0.00091%
Both far below BS1 threshold of 0.3%

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS4 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. Details ▾Hide ▴

Evidence considered

No reports of non-segregation in affected families

BP2 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. Details ▾Hide ▴

Evidence considered

No cis or trans observations meeting BP2 criteria
B3GALT6 disease is autosomal recessive

BP4 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.03 (no splice impact)
No additional benign computational predictors applicable

Sources

spliceai ↗

Not assessed · 9 · no assessment recorded

PS3 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. Details ▾Hide ▴

Evidence considered

REVEL/BayesDel skipped for non-SNV
No variant-specific functional assays identified

Still missing

Functional studies (e.g.
galactosyltransferase-II activity assay) on this specific variant would be needed

Sources

25741868

PS4 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 1/139
512 alleles (AF=7.17e-06)
gnomAD v4.1: 14/1
544
998 alleles (AF=9.06e-06)
No verified publications with variant counts in affected cases

Still missing

Verified publication counts of c.901_904dup in affected individuals vs controls
PMID:23664117 claims could not be verified
human curator should review

Sources

gnomad_v2 ↗gnomad_v4 ↗

PM1 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). Details ▾Hide ▴

Evidence considered

Not in a statistically significant cancer hotspot region
No B3GALT6-specific domain-level PM1 framework available

Still missing

Gene-specific functional domain mapping for B3GALT6 would be needed

PP1 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. Details ▾Hide ▴

Evidence considered

Claims from exploratory agent about PMID:23664117 could not be verified

Still missing

Verified segregation data from publications
human curator should retrieve and review PMID:23664117 full text

Sources

23664118

PP4 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. Details ▾Hide ▴

Still missing

Patient phenotype information not provided in the case

BS2 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 0 homozygotes
gnomAD v4.1: 0 homozygotes
B3GALT6 disease is autosomal recessive

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 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. Details ▾Hide ▴

Still missing

Functional studies showing normal galactosyltransferase-II activity for this variant

Sources

25741868

BP5 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. Details ▾Hide ▴

Still missing

Case-level data on alternative molecular diagnoses

BP6 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. Details ▾Hide ▴

Evidence considered

ClinVar: no benign or likely benign submissions

Sources

clinvar ↗

Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 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. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 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. Details ▾Hide ▴

Evidence considered

Variant type is frameshift duplication
not in-frame

PM5 N/APM5 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). Details ▾Hide ▴

Evidence considered

No same-residue missense comparator candidates identified

PP2 N/APP2 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. Details ▾Hide ▴

No further detail was recorded.

PP5 N/APP5 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. Details ▾Hide ▴

Evidence considered

ClinVar Variation ID 1323966: 2 LP
2 VUS
no expert panel
No reputable source with definitive pathogenic classification

Sources

clinvar ↗

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism. This variant is a frameshift, not a missense change. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 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. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a frameshift duplication, not a synonymous change. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 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. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: B3GALT6
Transcript: NM_080605.4
Coding (HGVS c.): NM_080605.4:c.901_904dup
Protein (HGVS p.): NP_542172.2:p.(Arg302GlnfsTer142)
GRCh38: chr1:1233176 T>TGCAA
GRCh37: chr1:1168556 T>TGCAA
ClinVar: 1323966

Gene diagram

Every interpreted variant in B3GALT6, mapped onto the exon structure of NM_080605.4. Select a row to find it on the plot.

B3GALT6NM_080605.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in B3GALT6 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 14 / 1,544,998 alleles AF 9.06e-06 · 0 homozygotes · FAF 6.31e-06

gnomAD v2.1 1 / 139,512 alleles AF 7.17e-06 · 0 homozygotes

gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 9.1e-06 · 14 / 1,544,998 alleles · 0 hom · FAF 6.3e-06

Admixed American1 / 51,556	1.9e-05
European (non-Finnish)13 / 1,149,594	1.1e-05

0 alternate alleles recorded in 8 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 7.2e-06 · 1 / 139,512 alleles · 0 hom

European (non-Finnish)1 / 52,794

1.9e-05

0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 9.0615e-06; MAF= 0.00091%, 14/1544998 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.93964e-05; MAF= 0.00194%, 1/51556 alleles, homozygotes = 0); grpmax FAF= 6.31e-06.

gnomAD v2.1

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -178 bp

0.010

SpliceAI acceptor gainat +396 bp

0.010

SpliceAI donor lossat +485 bp

0.010

SpliceAI donor gainat +11 bp

0.030

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.020

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI: max delta = 0.03 (no significant splice impact)
REVEL: not applicable (non-SNV)
BayesDel: not applicable (non-SNV)
HCI prior: gene not supported

Sources

spliceai ↗

Evidence considered

SpliceAI max delta = 0.03 (no splice impact)
No additional benign computational predictors applicable

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a frameshift duplication, not a synonymous change. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

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.

Richards S et al. · 2015

No paper-specific finding is recorded.

PMID 25741868 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K et al. · 2017

No paper-specific finding is recorded.

PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 14 / 1,544,998 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.030 Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

ClinVar

This variant is present in ClinVar (Variation ID: 1323966); submission details unavailable.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.