B3GALT6c.902_905dupUncertain significance

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Variant interpretation report

B3GALT6 c.902_905dup, p.(Glu303AlafsTer141)

NM_080605.4:c.902_905dup NP_542172.2:p.(Glu303AlafsTer141) 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: 2 moderate (pathogenic)
Expert rules: Not recorded
Pipeline record: 8 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PVS1 (moderate): 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.
PM2 (moderate): 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.

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

PVS1Moderate

PVS1 · moderate

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.

PM2Moderate

PM2 · moderate

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.

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 moderate, PM2 moderate; combination = 2 moderate, 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

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

Applied · PM2 →

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

SpliceAI score

0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. 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.

29 criteria with recorded statuses: 2 met · 4 not met · 15 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 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.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).

Met · 2

PVS1 ModerateNM_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. Details ▾Hide ▴

Evidence considered

Frameshift variant predicted to yield NP_542172.2:p.(Glu303AlafsTer141)
B3GALT6 LoF established as disease mechanism for autosomal recessive EDS-like connective tissue disorder
NM_080605.4 is MANE Select
single-exon gene — NMD escape expected
Downgraded to PVS1_Moderate per PMC6185798 due to NMD escape in single-exon gene

Still missing

Single-exon gene
NMD escape prevents Very Strong or Strong PVS1. Human review may consider whether the C-terminal alteration is extensive enough to warrant PVS1_Strong.

Sources

pvs1_generic_framework ↗23664118

PM2 ModerateNM_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. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (0 alleles)
Absent from gnomAD v4.1 (0 alleles)
Absent from gnomAD-Canada v1.0 (0 alleles)

Sources

gnomad_v2 ↗gnomad_v4 ↗

Not met · 4 · evaluated, threshold not reached

PP3 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.02 (no significant splice impact)
REVEL not available (not an SNV)
BayesDel not available (not an SNV)
HCI Prior not available (gene not supported)

Sources

spliceai ↗

BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency = 0.0), far below the BA1 threshold of >1%. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF = 0.0
gnomAD v4.1 AF = 0.0
gnomAD-Canada AF = 0.0

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 This variant is absent from all population databases (AF = 0.0), failing to meet the BS1 threshold of >0.3% allele frequency. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF = 0.0
gnomAD v4.1 AF = 0.0
gnomAD-Canada AF = 0.0

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP4 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.02 (no splice impact
but not exculpatory for a frameshift)
REVEL/BayesDel/HCI Prior not applicable to non-SNV variants

Sources

spliceai ↗

Not assessed · 15 · no assessment recorded

PS2 No de novo data with confirmed paternity and maternity available for this variant. Details ▾Hide ▴

Still missing

No de novo observations identified for NM_080605.4:c.902_905dup.

PS3 No well-established in vitro or in vivo functional studies specific to NM_080605.4:c.902_905dup are available. Details ▾Hide ▴

Still missing

No functional assay data for this specific variant.

PS4 No case-control data demonstrating statistically increased prevalence of this variant in affected individuals versus controls is available. Details ▾Hide ▴

Still missing

No case-control or cohort data for NM_080605.4:c.902_905dup.

PM1 No data demonstrating that this variant lies within a well-established mutational hotspot or critical functional domain with supporting statistical evidence is available. Details ▾Hide ▴

Still missing

No hotspot or critical domain data for this residue in B3GALT6.

PM6 No assumed de novo observation (without parental confirmation) is available for this variant. Details ▾Hide ▴

Still missing

No de novo reports identified for NM_080605.4:c.902_905dup.

PP1 No cosegregation data in multiple affected family members is available for this variant. Details ▾Hide ▴

Still missing

No family segregation data available.

PP4 No patient phenotype or family history data specific to this variant is available. Details ▾Hide ▴

Still missing

No proband phenotype data available.

PP5 This variant is absent from ClinVar; no reputable source has reported it as pathogenic. Details ▾Hide ▴

Still missing

Variant not present in ClinVar.

BS2 No data on observation of this variant in healthy adult individuals for a fully penetrant disorder is available. Details ▾Hide ▴

Still missing

No observation in healthy adult controls beyond population databases.

BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect for this specific variant are available. Details ▾Hide ▴

Still missing

No benign functional assay data for NM_080605.4:c.902_905dup.

BS4 No segregation data demonstrating lack of cosegregation with disease in affected family members is available. Details ▾Hide ▴

Still missing

No family segregation data available.

BP2 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. Details ▾Hide ▴

Still missing

No phase data available for this variant.

BP5 No data on an alternate molecular basis for disease in a case carrying this variant is available. Details ▾Hide ▴

Still missing

No alternate molecular diagnosis data.

BP6 This variant is absent from ClinVar; no reputable source has reported it as benign. Details ▾Hide ▴

Still missing

Variant not present in ClinVar.

PS5 No data on this variant observed in trans with a known pathogenic variant in B3GALT6 is available. Details ▾Hide ▴

Still missing

No trans-phase observations available.

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 applies to same amino acid changes arising from different nucleotide substitutions; not applicable to a 4bp duplication producing a frameshift. Details ▾Hide ▴

No further detail was recorded.

PM3 N/APM3 skipped per explicit instruction — criterion marked as trivially not_applicable. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 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. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 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). Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation. NM_080605.4:c.902_905dup is a frameshift variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 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. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. NM_080605.4:c.902_905dup is a frameshift variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_080605.4:c.902_905dup is a frameshift duplication. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: B3GALT6
Transcript: NM_080605.4
Coding (HGVS c.): NM_080605.4:c.902_905dup
Protein (HGVS p.): NP_542172.2:p.(Glu303AlafsTer141)
GRCh38: chr1:1233179 A>AAGCG
GRCh37: chr1:1168559 A>AAGCG

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 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

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

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -181 bp

0.010

SpliceAI acceptor gainat +393 bp

0.010

SpliceAI donor lossat +482 bp

0.010

SpliceAI donor gainat +8 bp

0.020

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.030

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta = 0.02 (no significant splice impact)
REVEL not available (not an SNV)
BayesDel not available (not an SNV)
HCI Prior not available (gene not supported)

Sources

spliceai ↗

Evidence considered

SpliceAI max delta = 0.02 (no splice impact
but not exculpatory for a frameshift)
REVEL/BayesDel/HCI Prior not applicable to non-SNV variants

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_080605.4:c.902_905dup is a frameshift duplication. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

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

SpliceAI Lookup Recorded maximum delta 0.020 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

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

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.