Source label and VCEP threshold result differ
Reference transcript: . ARIANE derives and verifies canonical c. and three-letter p. HGVS locally. Genome assembly is not needed for c. HGVS. Select GRCh37 or GRCh38 for the genomic coordinate.
Select Confirmed tandem only when supported by laboratory data. Otherwise keep Unknown.
Points
Reference transcript:
Submitted as:
Why is the protein consequence unknown?
Total points:
Calibrated functional evidence available in ENIGMA Table 9
Mixed evidence.
Pathogenic and benign evidence co-occur. ENIGMA v1.2 second classification approach,
using Tavtigian 2020 points, was applied. Expert review required.
ENIGMA v1.2, Classification Methods, second approach
Applied criteria
| Criterion | Strength | Points | Reason |
|---|---|---|---|
|
|
|||
Not applicable to this variant () Show codes and reasons
These outcomes were explicitly marked as not applicable by the variant-specific ENIGMA decision path. Criteria that were not met, unavailable, or excluded are not included here.
Open official VCEP specificationCriteria excluded by an ENIGMA exception
The numerical threshold was met, but the criterion was not applied and added no points.
| Criterion | Threshold strength | Points | Why it was not applied |
|---|---|---|---|
| 0 (not counted) | ENIGMA source |
AlphaMissense
(informational only - not included in ENIGMA VCEP scoring)
Suggested review:
Why it was flagged
What RNA evidence should document
Potential ENIGMA branches:
Open ENIGMA specificationWhy it was flagged
What to check
Potential ENIGMA branch:
Reference source:
Open ENIGMA specificationNext step: ARIANE has prefilled the Protein PS1 manual review and is checking ClinVar and ClinGen for an official ENIGMA VCEP assertion. Review the remaining unconfirmed fields before submitting manual evidence.
Why it was flagged
What to check
| Reference candidate | Class | Status | Source |
|---|---|---|---|
RNA/splice sources checked for the assessed variant:
Open ENIGMA specificationWhy it was flagged
What to check
Potential ENIGMA branch:
Reference source:
Open ENIGMA specificationEvidence details
Variant normalization
- Method
- Engine
- Engine version
- Provider
- cdot data release
- Reference bundle
- Reference manifest checksum
PP4/BP5 clinical likelihood ratios
- ENIGMA data release
- LR used for classification
- LR data status
- Published combined LR
- Source track label
- VCEP threshold result
- VCEP rule used
- Publisher-combined source bundles
| Source | Clinical data | Component LR | PMID |
|---|---|---|---|
gnomAD population frequency policy Frequency, coverage and founder review
Founder exception review: .
PM2 coverage method: .
Scored ENIGMA non-founder populations: . Founder and other excluded groups do not contribute to BA1, BS1 or PM2 presence.
Coverage mean depth: . Classification compatible: .
| Scored population | AC / AN | FAF95 |
|---|---|---|
| Excluded context group | AC / AN | AF | FAF95 | Reason |
|---|---|---|---|---|
SpliceAI
- Status
- Score used
- ENIGMA scoring profile
- Genome assembly
- Maximum distance
- Masking
- Annotation subset
- Aggregation
- Transcript used
- Transcript policy
- Reference transcript score
- Maximum across all transcripts
- Transcript with overall maximum
- Maximum delta field
- Delta scores
- Reference scores
- Alternate scores
- Source
- GRCh38 query
- Cache record
- Lookup information
Mixed evidence combination ENIGMA v1.2 / Tavtigian 2020 points
- Pathogenic points
- Benign points
- Total
- Method
- ENIGMA VCEP v1.2 second classification approach for mixed evidence, using the Tavtigian 2020 point system
Manually reviewed criteria
Add evidence that cannot be automated. The original Module 1 result remains unchanged; ARIANE calculates a separate amended working result.
Recommended reviews for this variant
ARIANE found variant-specific evidence that can be carried into expert review.
ARIANE threshold:
A reported combined LR is sufficient to derive BS4 strength. To let BS4 Strong qualify as the sole Strong code for Likely Benign under ENIGMA Table 3, record at least two independent LR components. Their product must equal the reported combined LR.
Required when PP1 or PS4 is combined with PP4/BP5. Do not confirm independence without reviewing the underlying clinical LR components.
Select the scale exactly as reported. Do not enter a log10 likelihood ratio as an ordinary LR.
This source will be retained in the audit record but cannot add clinical LR evidence points.
Clinical evidence types contributing to the combined LR
This record is required before BP5 Strong can serve as the single Strong route to Likely Benign. BP5 points may still be valid without that single-criterion route.
Assessed variant facts
This criterion is already present from ENIGMA Table 9 and cannot be counted again manually.
Variant identity, transcript, variant type and available SpliceAI context are prefilled. ARIANE does not infer a new functional strength from those facts. The reviewer must document the ENIGMA-compatible assay calibration.
ARIANE checks BP7 Strong (RNA) against the classified variant. A missense variant inside an ENIGMA functional domain must meet BS3 through calibrated Table 9 evidence or the complete manual BS3 review above. This condition cannot be confirmed by a standalone checkbox.
Why PS1 cannot be assigned from ST2 alone
ENIGMA additionally requires:
- a reference P/LP classification assigned using VCEP specifications;
- precisely the same splice event in the assessed and reference variants;
- a splice prediction for the assessed variant that is similar to or stronger than the reference prediction;
- the correct Appendix J/Table 17 branch based on the positions of both variants within the donor or acceptor motif;
- the assessed variant's baseline PP3 or PVS1 result to be included in the Table 17 decision;
- review of any concurrent protein-level consequence for an exonic variant.
ARIANE therefore leaves same-event confirmation, prediction comparison and PS1 strength for manual review.
Enter c. HGVS, for example c.5217T>G.
Defined sources: . “None identified” means only that these recorded sources were checked; it is not an absolute claim that no splice evidence exists.
Prefilled facts: Variant identity, protein consequence, ST7 candidate classification, available SpliceAI results and recorded ENIGMA RNA/splice source checks are completed automatically where data are available. A historical ST7 classification remains non-scoring until an ENIGMA/ClinGen VCEP assertion or a documented local reclassification is selected and supported.
ClinVar review stars describe the review status of a submitted classification. They do not establish that the reference was classified under the applicable ENIGMA VCEP specifications. Using the ClinVar aggregate conclusion itself as proof of the reference classification would be circular. ARIANE therefore does not copy an ordinary ClinVar aggregate classification, verification, source, or reference into the PS1 evidence record.
Criterion strength is calculated by the backend after the evidence is submitted.
Do not enter names, dates of birth or other direct patient identifiers in evidence notes.
Working result including user-provided evidence
Total points:
This amended result is audit support, not an independent clinical classification. The reviewer remains responsible for evidence validity and applicability.
| Criterion | ARIANE suggestion | Selected strength | Points |
|---|---|---|---|
Assessor: ; date:
Saving and approval require the authenticated reviewer account configured for this ARIANE installation. The current beta uses the protected administrator account and records both the account and the stated reviewer identity.
Version ;
record
Content SHA-256:
Approve this saved version
Approval creates a new immutable version. The saved draft is retained unchanged.
Warnings
External comparison ClinVar and ENIGMA Expert Panel
ClinVar
| Aggregate classification | |
| Review status | |
| ClinVar review stars | |
| Submitters | |
| Conflict | Yes - conflicting interpretations |
Submitter details
| Submitter | Classification | Date | Review | Curated status |
|---|---|---|---|---|
ENIGMA Expert Panel
| ENIGMA EP classification | |
| Source |
ENIGMA rules used by ARIANE
ClinGen ENIGMA BRCA1/2 VCEP , released .
Loading validated rules and data sources...
The coloured nodes and connectors show the path used for the selected applied criterion.
Selected variant path
Show path for:
General rule view. Classify a variant, then open a criterion's decision path to highlight the route supported by its evidence. General view of this branch. The selected variant follows the branch.
Variant type
Decision
Outcome
Path used for this result
Key
Original ENIGMA figures
Original panels extracted from the checksum-validated ENIGMA Specifications and Appendix v1.2 documents.
ENIGMA tables
ENIGMA tables used by ARIANE are shown first. The complete -table v1.2 source bundle remains available for expert review and audit.
ARIANE use:
Loading table rows...
| Row | |
|---|---|
No rows match this search.
rows,
page of
Validated sources and versions
Checksums identify the exact official files used to build and verify ARIANE data. Local server paths are not exposed.
- Version
- SHA256
- Runtime records
Enter one variant per line. Both formats are accepted:
BRCA1, c.509G>A <-- gene and reference-transcript c. HGVS BRCA1, NM_007294.4:c.303T>G <-- transcript-qualified HGVS BRCA1, chr17:43099813:C>T, GRCh38 <-- genomic variant requires assembly BRCA1, c.509G>A, p.(Arg170Gln) <-- comma-separated input BRCA1 NM_007294.4:c.509G>A p.(Arg170Gln) <-- space-separated input
A header row starting with gene or # is skipped automatically.
Results ( classified, errors)
| # | Gene | c. notation | p. notation | Class | Points | Criteria | Review | Warnings | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|