About TSC1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TSC1 c.2209-1G>C, p.?
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.
Words with a dotted underline have a short definition. Hover or tap them.
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
PVS1Very strong
PVS1 · very strong
This canonical splice acceptor variant (c.2209-1G>C, intron 16/exon 17 boundary) disrupts the AG dinucleotide at position -1. TSC1 loss of function is an established germline disease mechanism for tuberous sclerosis complex. Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants in genes with established LOF mechanisms are assigned PVS1 at very strong weight. SpliceAI predicts acceptor loss (delta score 0.99), confirming the predicted splicing defect. The affected exon (17 of 23) is not a biologically irrelevant distal exon or enriched for population LOF variation, and NMD is expected if exon skipping causes a frameshift.
PM2Supporting
PM2 · supporting
This variant is completely absent from all population databases, including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada. Under generic ACMG/AMP 2015, PM2 is applied at supporting level for variants with an allele frequency below 0.1% in population databases.
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 very strong, PM2 supporting; combination = 1 very 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.990 maximum delta
Recorded SpliceAI maximum delta score: 0.990. 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 ↗
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV53774227, n = 2 times).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 18 not met · 1 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000368.4:c.2209-1G>C disrupts the canonical splice acceptor site at the intron 16/exon 17 boundary of TSC1, a gene in which loss of function is an established mechanism for autosomal dominant tuberous sclerosis complex.
Under ClinGen SVI PVS1 recommendations (PMC6185798), this canonical ±1 splice variant qualifies for PVS1 at very strong weight. SpliceAI predicts acceptor loss with a delta score of 0.99. The affected exon (17 of 23) is predicted to cause a frameshift and NMD if skipped, with no evidence of alternative splicing or population LOF enrichment.
The variant is absent from all population databases (gnomAD v2.1, v4.1, Canada), meeting PM2 at supporting level under generic ACMG/AMP 2015 (<0.1% cutoff).
No additional pathogenic or benign criteria are met. PS3, PM1, PP5, and all other assessed criteria are not met or not applicable due to absence of variant-specific clinical, functional, or literature evidence.
Under generic ACMG/AMP 2015 final combination rules (PMID:25741868), PVS1 (very strong) + PM2 (supporting) does not meet the threshold for Likely Pathogenic (requires 1 very strong + 1 moderate, or 1 strong + 2 supporting). The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PVS1 Very strongThis canonical splice acceptor variant (c.2209-1G>C, intron 16/exon 17 boundary) disrupts the AG dinucleotide at position -1. TSC1 loss of function is an established germline disease mechanism for tuberous sclerosis complex. Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical ±1,2 splice variants in genes with established LOF mechanisms are assigned PVS1 at very strong weight. SpliceAI predicts acceptor loss (delta score 0.99), confirming the predicted splicing defect. The affected exon (17 of 23) is not a biologically irrelevant distal exon or enriched for population LOF variation, and NMD is expected if exon skipping causes a frameshift. Details ▾Hide ▴
Evidence considered
- Canonical splice acceptor site disruption at c.2209-1 (AG → AC)
- TSC1 germline LOF mechanism established via literature (tuberous sclerosis complex)
- SpliceAI delta score 0.99 (acceptor loss) confirms predicted splicing defect
- Exon 17 skipping predicted to cause frameshift and NMD
- no evidence of alternative splicing or population LOF enrichment at this exon
Still missing
- Functional RNA studies confirming aberrant splicing and NMD would strengthen the evidence
- No VCEP/CSPEC framework available for TSC1 to provide gene-specific PVS1 calibration
Sources
PM2 SupportingThis variant is completely absent from all population databases, including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada. Under generic ACMG/AMP 2015, PM2 is applied at supporting level for variants with an allele frequency below 0.1% in population databases. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes)
- Absent from gnomAD-Canada v1.0 (genomes)
Sources
Not met · 18 · evaluated, threshold not reached
PS1 No known pathogenic variant at the same nucleotide position with the same predicted effect has been identified. PS1 requires a different nucleotide change at the same position producing the same amino acid change, which is not applicable to this splice variant without another established pathogenic splice variant at c.2209-1. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no known pathogenic comparator at c.2209-1
Sources
PS2 No de novo data are available for this variant. No family studies or parentage testing has been identified. Details ▾Hide ▴
Evidence considered
- No literature or database entries report de novo occurrence for this variant
Still missing
- De novo confirmation would require parental testing data
PS3 No variant-specific functional data are available for NM_000368.4:c.2209-1G>C. No experimental studies directly testing this splice variant or systematically characterizing the splice acceptor region were identified in the evidence. Details ▾Hide ▴
Evidence considered
- No literature
- database
- or full-text evidence identified for variant-specific functional data
Still missing
- RNA studies (RT-PCR
- minigene assay) would be needed to demonstrate aberrant splicing and functional consequence
PS4 No case-control or cohort data are available for this variant. Absent from ClinVar and not reported in any literature as a clinically observed variant in affected individuals. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no case reports or cohort studies identified
Still missing
- Clinical observation in affected TSC patients would be required to meet PS4
Sources
PM1 While the variant disrupts splicing within the TSC1 coiled-coil domain (residues ~717-997), which is critical for TSC1-TSC2 interaction, no specific domain-level PM1 framework has been established for TSC1 by a VCEP, and cancerhotspots.org does not identify this residue as significant. The functional domain argument is plausible but cannot be formally applied under generic ACMG without curated domain boundaries. Details ▾Hide ▴
Evidence considered
- TSC1 coiled-coil domain is functionally characterized in the literature but no formal PM1 domain map exists for generic ACMG application
Still missing
- A VCEP-defined PM1 domain map for TSC1 would enable formal application
PM6 No de novo data are available for this variant. PM6 requires confirmation that the variant arose de novo with both maternity and paternity confirmed. Details ▾Hide ▴
Evidence considered
- No literature or database entries report de novo occurrence
Still missing
- Parental testing data would be required
PP1 No segregation data are available for this variant. PP1 requires cosegregation with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No family or segregation studies identified
Still missing
- Family studies with segregation analysis would be required
PP3 In silico splice predictions (SpliceAI delta 0.99, acceptor loss) strongly support a damaging splicing effect, but this evidence is already captured by PVS1 for a canonical splice site variant. Under PMC6185798 guidance, PP3 should not be stacked on top of PVS1 for the same splice-effect prediction. BayesDel score (0.313) does not independently predict a damaging effect. Details ▾Hide ▴
Evidence considered
- SpliceAI delta 0.99 — accounted for within PVS1
- double-counting prohibited by PMC6185798
- BayesDel 0.313 — below damaging threshold
Sources
PP5 This variant is absent from ClinVar. PP5 requires a reputable source (preferably ClinVar 3-star expert panel) to have classified the variant as pathogenic. No such classification exists. Details ▾Hide ▴
BA1 The variant is absent from all gnomAD population databases. BA1 requires an allele frequency exceeding 1%, which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and Canada
Sources
BS1 The variant is absent from all gnomAD population databases. BS1 requires an allele frequency exceeding 0.3%, which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and Canada
Sources
BS2 No data on homozygous or hemizygous occurrence in healthy adults are available. The variant is absent from all population databases. Details ▾Hide ▴
Evidence considered
- No homozygous observations in gnomAD
- variant entirely absent from population databases
BS3 No well-established functional studies demonstrate a benign effect for this variant. No experimental data of any kind were identified. Details ▾Hide ▴
Evidence considered
- No functional data available for this variant
Still missing
- RNA or protein functional studies would be required to assess BS3
BS4 No segregation data are available. BS4 requires lack of segregation with disease in affected family members, which requires family-based genotype and phenotype data. Details ▾Hide ▴
Evidence considered
- No family or segregation studies identified
Still missing
- Family segregation data would be required
BP2 No data on observations in trans with a pathogenic variant for TSC1 (autosomal dominant disorder) or in cis with a known pathogenic variant are available. Details ▾Hide ▴
Evidence considered
- No phase data available
BP4 Multiple lines of computational evidence do NOT suggest a benign impact. SpliceAI predicts a strong splice-disrupting effect (delta 0.99, acceptor loss). BayesDel (0.313) does not independently predict benign impact. The weight of in silico evidence favors a damaging effect. Details ▾Hide ▴
Evidence considered
- SpliceAI delta 0.99 predicts strong splicing disruption (contradicts BP4)
- BayesDel 0.313 — not strongly benign
Sources
spliceai ↗bayesdel
BP5 No data on an alternative molecular basis for disease are available. BP5 requires the variant to be found in a case with an established alternative genetic cause for the phenotype. Details ▾Hide ▴
Evidence considered
- No alternative molecular diagnosis data available
Still missing
- Clinical data with alternative genetic diagnosis would be required
BP6 This variant is absent from ClinVar. BP6 requires a reputable source to have classified the variant as benign. No such classification exists. Details ▾Hide ▴
Not assessed · 1 · no assessment recorded
PP4 No patient phenotype or clinical data are available for this case. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Tuberous sclerosis complex has a recognizable clinical presentation, but without patient-specific phenotype data, PP4 cannot be assessed. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data provided for the proband
Still missing
- Patient phenotype data would be needed to assess specificity for TSC
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PM5 N/APM5 applies only to missense variants where a different pathogenic amino acid change has been observed at the same residue. This variant is a canonical splice site substitution affecting the intron 16/exon 17 boundary, not a missense change. Protein consequence cannot be determined (NP_000359.1:p.?). Details ▾Hide ▴
Evidence considered
- Splice variant with unknown protein consequence (p.?)
- no same-residue comparator semantics available
Sources
pm5_candidates
PP2 N/APP2 applies specifically to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. This variant is a canonical splice site substitution, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. This is a canonical splice site variant disrupting normal splicing, predicted to result in a truncating effect, not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants for which splicing prediction algorithms predict no impact on the splice consensus sequence. This variant is a canonical splice site substitution (c.2209-1G>C) with SpliceAI predicting strong splice disruption (delta 0.99). Details ▾Hide ▴
Evidence considered
- Not a synonymous variant
- canonical splice site variant with predicted strong impact
Sources
PS5 N/APS5 applies only to novel missense variants at a residue where a different pathogenic missense change has been established. This is a splice site variant, not a missense substitution. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- TSC1
- Transcript
- NM_000368.4
- Coding (HGVS c.)
- NM_000368.4:c.2209-1G>C
- Protein (HGVS p.)
- NP_000359.1:p.?
- GRCh38
- chr9:132902788 C>G
- GRCh37
- chr9:135778175 C>G
- COSMIC
- COSV53774227
Gene diagram
Every interpreted variant in TSC1, mapped onto the exon structure of NM_000368.4. Select a row to find it on the plot.
TSC1NM_000368.4
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 TSC1
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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
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- 0.313
How the predictions were used
PP3 In silico splice predictions (SpliceAI delta 0.99, acceptor loss) strongly support a damaging splicing effect, but this evidence is already captured by PVS1 for a canonical splice site variant. Under PMC6185798 guidance, PP3 should not be stacked on top of PVS1 for the same splice-effect prediction. BayesDel score (0.313) does not independently predict a damaging effect. Details ▾Hide ▴
Evidence considered
- SpliceAI delta 0.99 — accounted for within PVS1
- double-counting prohibited by PMC6185798
- BayesDel 0.313 — below damaging threshold
Sources
BP4 Multiple lines of computational evidence do NOT suggest a benign impact. SpliceAI predicts a strong splice-disrupting effect (delta 0.99, acceptor loss). BayesDel (0.313) does not independently predict benign impact. The weight of in silico evidence favors a damaging effect. Details ▾Hide ▴
Evidence considered
- SpliceAI delta 0.99 predicts strong splicing disruption (contradicts BP4)
- BayesDel 0.313 — not strongly benign
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous variants for which splicing prediction algorithms predict no impact on the splice consensus sequence. This variant is a canonical splice site substitution (c.2209-1G>C) with SpliceAI predicting strong splice disruption (delta 0.99). Details ▾Hide ▴
Evidence considered
- Not a synonymous variant
- canonical splice site variant with predicted strong impact
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.312875.
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 0.990
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000368.4%3Ac.2209-1G%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-135778175-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-132902788-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-132902788-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000368.4%3Ac.2209…
- OncoKB ↗www.oncokb.org/gene/TSC1/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=122165001
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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.312875.
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV53774227, n = 2 times).