About TSC1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
TSC1 c.1438+6G>A, 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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_000368.5:c.1438+6G>A is present in gnomAD at very low allele frequency: 0.00999% (28/280,414 alleles, no homozygotes) in v2.1 and 0.01508% (243/1,611,274 alleles, no homozygotes) in v4.1, with grpmax filtering AF of 0.000147 (v2.1) and 0.000179 (v4.1). The allele frequency is well below the 0.1% threshold for PM2 in a dominant disorder gene.
Benign criteria applied · 1
BP6Supporting
BP6 · supporting
BP6 applies when a reputable source reports the variant as benign with supporting evidence not independently available. ClinVar aggregate classification (ID 48782) for NM_000368.5:c.1438+6G>A is conflicting but predominantly benign: 10 of 15 clinical laboratory submissions classify the variant as Benign (3 submissions), Likely benign (7 submissions), or Likely Benign (1 submission), with only 1 Uncertain significance submission. The weight of clinical laboratory consensus supports application of BP6 at supporting benign strength. No expert panel has reviewed this variant.
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: PM2 supporting, BP6 supporting benign; combination = 1 supporting + 1 supporting benign, 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
243 / 1,611,274 alleles
gnomAD v4.1: 243 / 1,611,274 alleles. Recorded AF 0.000150812. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 9.98524e-05; MAF= 0.00999%, 28/280414 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000203669; MAF= 0.02037%, 26/127658 alleles, homozygotes = 0); grpmax FAF= 0.00014731.
SpliceAI score
0.100 maximum delta
Recorded SpliceAI maximum delta score: 0.100. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
13 reported laboratory submissions
7 Likely benign · 3 Benign · 1 Likely Benign · 1 Uncertain significance · 1 benign.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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 · 7 not met · 11 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000368.5:c.1438+6G>A is present in gnomAD at very low allele frequency (0.010% in v2.1, 0.015% in v4.1; 28–243 alleles, no homozygotes), meeting PM2 at supporting strength.
The variant is reported in ClinVar (ID 48782) with 10 of 15 clinical laboratory submissions classifying as Benign or Likely Benign, meeting BP6 at supporting benign strength. No submission classifies as Pathogenic.
SpliceAI predicts no significant splicing impact (max delta score 0.10). No other computational or functional evidence supports or refutes a deleterious effect.
PS2 (de novo), PS3 (functional), PS4 (case-control), PM6 (assumed de novo), PP1 (cosegregation), PP4 (patient phenotype), BS2 (healthy adults), BS3 (benign functional), BS4 (lack of segregation), BP2 (in trans/cis), and BP5 (alternate molecular basis) could not be assessed due to absence of variant-specific clinical or functional data.
PVS1 is not met: the variant is at the +6 intronic position outside canonical ±1,2 splice sites, and SpliceAI does not predict a splice alteration. The variant does not qualify as a predicted null variant under ClinGen SVI PVS1 recommendations.
Using the generic ACMG/AMP 2015 combination rules (PMID:25741868), the variant has one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP6). The net point score is 0, resulting in a classification of Variant of Uncertain Significance (VUS). This is consistent with the conflicting ClinVar aggregate classification.
No criteria match.
Met · 2
PM2 SupportingNM_000368.5:c.1438+6G>A is present in gnomAD at very low allele frequency: 0.00999% (28/280,414 alleles, no homozygotes) in v2.1 and 0.01508% (243/1,611,274 alleles, no homozygotes) in v4.1, with grpmax filtering AF of 0.000147 (v2.1) and 0.000179 (v4.1). The allele frequency is well below the 0.1% threshold for PM2 in a dominant disorder gene. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 28/280
- 414 alleles (AF=0.010%)
- 0 homozygotes
- gnomAD v4.1: 243/1
- 611
- 274 alleles (AF=0.015%)
- grpmax FAF v2.1=0.000147
- v4.1=0.000179 — both below PM2 threshold
- Highest subpopulation: European (non-Finnish) AF=0.020%
Sources
BP6 SupportingBP6 applies when a reputable source reports the variant as benign with supporting evidence not independently available. ClinVar aggregate classification (ID 48782) for NM_000368.5:c.1438+6G>A is conflicting but predominantly benign: 10 of 15 clinical laboratory submissions classify the variant as Benign (3 submissions), Likely benign (7 submissions), or Likely Benign (1 submission), with only 1 Uncertain significance submission. The weight of clinical laboratory consensus supports application of BP6 at supporting benign strength. No expert panel has reviewed this variant. Details ▾Hide ▴
Evidence considered
- ClinVar ID 48782: 10/15 submissions Benign or Likely Benign
- Multiple clinical laboratories: Labcorp/Invitae (Benign)
- GeneDx (Likely benign)
- Color Health (Likely benign)
- Quest Diagnostics (benign)
- All of Us (Likely Benign)
- Genome-Nilou Lab (Benign)
- CeGaT (Likely benign)
- and others
- 1 submission Uncertain significance
- no Pathogenic submissions
- Review status: criteria provided
- conflicting classifications
Sources
Not met · 7 · evaluated, threshold not reached
PVS1 NM_000368.5:c.1438+6G>A is an intronic variant at the donor splice site +6 position, outside the canonical ±1,2 splice consensus. SpliceAI max delta score is 0.10, predicting no significant splice impact. The variant does not qualify as a predicted null variant under the ClinGen SVI PVS1 decision framework (PMC6185798); generic PVS1 framework application is not indicated. Details ▾Hide ▴
Evidence considered
- Intronic +6 position does not meet canonical splice consensus criteria for PVS1
- SpliceAI max delta 0.10 — no predicted splice alteration
- TSC1 loss-of-function is an established disease mechanism but variant type does not qualify as null
Sources
PM1 PM1 applies to variants located in a mutational hotspot or critical functional domain. NM_000368.5:c.1438+6G>A is intronic and does not map to a defined critical functional domain at the nucleotide or amino acid level. The donor splice region around TSC1 exon 14 is not a recognized mutational hotspot. Details ▾Hide ▴
Evidence considered
- Intronic position +6 does not map to a known mutational hotspot or critical domain
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. SpliceAI max delta score is 0.10, which does not predict a significant splicing impact (threshold ≥0.2). REVEL and BayesDel scores are unavailable as the variant is intronic. No in silico tool supports a damaging prediction. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.10 — below the 0.2 threshold for predicted splice impact
- REVEL and BayesDel not applicable to intronic variants
Sources
PP5 PP5 requires a reputable source to report the variant as pathogenic with supporting evidence. The ClinVar aggregate classification for this variant (ID 48782) is conflicting: 10 of 15 submissions classify as Benign or Likely Benign from multiple clinical laboratories, with 1 submission as Uncertain significance. No submission classifies as Pathogenic. The overall ClinVar conclusion does not meet PP5 criteria for a pathogenic assertion. Details ▾Hide ▴
Evidence considered
- ClinVar ID 48782: aggregate classification is conflicting
- 10/15 submissions: Benign (3) + Likely Benign (7)
- 1/15 submission: Uncertain significance
- No expert panel pathogenic classification
Sources
BA1 BA1 requires an allele frequency >1% in population databases. NM_000368.5:c.1438+6G>A has an allele frequency of 0.010–0.015% in gnomAD, far below the 1% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.010%
- v4.1 AF=0.015% — well below 1% threshold
Sources
BS1 BS1 requires an allele frequency >0.3% in population databases for a dominant disorder. NM_000368.5:c.1438+6G>A has an allele frequency of 0.010% (v2.1) and 0.015% (v4.1), below the 0.3% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.010%
- v4.1 AF=0.015% — below 0.3% BS1 threshold
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. SpliceAI max delta score of 0.10 does not predict a significant splicing alteration, consistent with a benign interpretation. However, ACMG/AMP guidance requires multiple independent lines of computational evidence; SpliceAI is the sole applicable in silico predictor for this intronic variant, and REVEL/BayesDel/HCI are unavailable. A single computational predictor does not meet the multiple-lines requirement for BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.10 — no predicted splice impact
- Only one computational line available
- BP4 requires multiple lines
Sources
Not assessed · 11 · no assessment recorded
PS2 PS2 requires a confirmed de novo occurrence with both parental relationships confirmed in a patient with the disease and no family history. No de novo reports for NM_000368.5:c.1438+6G>A were identified in ClinVar, literature, or de novo databases. Details ▾Hide ▴
Still missing
- No de novo observations found in any database or publication
PS3 PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect. No functional studies (RNA analysis, minigene assay, or protein-level evidence) were identified for NM_000368.5:c.1438+6G>A. Details ▾Hide ▴
Still missing
- No variant-specific functional studies available
- SpliceAI prediction alone does not constitute PS3-level evidence
PS4 PS4 requires statistically higher prevalence of the variant in affected individuals versus controls. No case-control study or cohort analysis demonstrating enrichment of NM_000368.5:c.1438+6G>A in tuberous sclerosis complex patients was identified. Details ▾Hide ▴
Still missing
- No case-control data available
- gnomAD presence alone insufficient for PS4
PM6 PM6 requires an assumed de novo occurrence without confirmation of paternity and maternity. No de novo reports for NM_000368.5:c.1438+6G>A were identified in any database or publication. Details ▾Hide ▴
Still missing
- No assumed de novo observations found
PP1 PP1 requires cosegregation of the variant with disease in multiple affected family members. No segregation data for NM_000368.5:c.1438+6G>A were identified in ClinVar or the literature. Details ▾Hide ▴
Still missing
- No family segregation data available
PP4 PP4 requires a patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. No individual patient phenotype data are available for NM_000368.5:c.1438+6G>A in the evidence record. Details ▾Hide ▴
Still missing
- No patient-level phenotype data available
BS2 BS2 requires observation of the variant in a healthy adult individual with full penetrance expected at an early age. No individual-level phenotype data confirming healthy adult carriers of NM_000368.5:c.1438+6G>A are available. Details ▾Hide ▴
Still missing
- No individual-level phenotype data for carriers
BS3 BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. No functional studies (splicing assays, RNA analysis, or protein-level experiments) were identified for NM_000368.5:c.1438+6G>A. Details ▾Hide ▴
Still missing
- No variant-specific functional studies available
BS4 BS4 requires lack of segregation of the variant with disease in affected family members. No family segregation data are available for NM_000368.5:c.1438+6G>A. Details ▾Hide ▴
Still missing
- No segregation data available
BP2 BP2 requires observation of the variant in trans with a known pathogenic variant in a fully penetrant dominant disorder, or in cis with a pathogenic variant. No such observations have been reported for NM_000368.5:c.1438+6G>A. Details ▾Hide ▴
Still missing
- No in trans or in cis observations available
BP5 BP5 requires identification of an alternate molecular basis for disease in a case where the variant was observed. No data on alternate molecular diagnoses in carriers of NM_000368.5:c.1438+6G>A are available. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 requires a same amino acid change as an established pathogenic variant. NM_000368.5:c.1438+6G>A is intronic with no protein-level consequence (p.?), rendering PS1 inapplicable. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 requires a novel missense change at the same amino acid residue as a known pathogenic missense variant. NM_000368.5:c.1438+6G>A is intronic with no protein-level consequence (p.?). PM5 candidate harvesting was automatically skipped due to unresolvable residue context. Details ▾Hide ▴
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and a high rate of pathogenic missense variants. NM_000368.5:c.1438+6G>A is intronic and does not produce a missense change. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where only truncating variants are known to cause disease. NM_000368.5:c.1438+6G>A is intronic and not a missense variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_000368.5:c.1438+6G>A is intronic, not synonymous. While SpliceAI predicts no splicing impact (delta 0.10), BP7 criteria are explicitly defined for synonymous coding variants and are not directly applicable to intronic variants. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a standard criterion in the ACMG/AMP 2015 generic framework (PMID:25741868). It is used only in select VCEP specifications. No TSC1 VCEP/CSPEC is available for this case. Additionally, the variant is intronic with no amino acid change. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- TSC1
- Transcript
- NM_000368.5
- Coding (HGVS c.)
- NM_000368.5:c.1438+6G>A
- Protein (HGVS p.)
- NP_000359.1:p.?
- GRCh38
- chr9:132906725 C>T
- GRCh37
- chr9:135782112 C>T
- ClinVar
- 48782
Gene diagram
Every interpreted variant in TSC1, mapped onto the exon structure of NM_000368.5. Select a row to find it on the plot.
TSC1NM_000368.5
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
243 / 1,611,274 alleles
AF 0.000151 · 0 homozygotes · FAF 0.000179
gnomAD v2.1
28 / 280,414 alleles
AF 9.99e-05 · 0 homozygotes · FAF 0.000147
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 0.00015 · 243 / 1,611,274 alleles · 0 hom · FAF 0.00018
| European (non-Finnish)236 / 1,177,978 | 0.0002 |
| Remaining individuals5 / 62,382 | 8e-05 |
| European (Finnish)1 / 63,936 | 1.6e-05 |
| South Asian1 / 90,784 | 1.1e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 0.0001 · 28 / 280,414 alleles · 0 hom · FAF 0.00015
| European (non-Finnish)26 / 127,658 | 0.0002 |
| European (Finnish)2 / 25,034 | 8e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, 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= 0.000150812; MAF= 0.01508%, 243/1611274 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000200343; MAF= 0.02003%, 236/1177978 alleles, homozygotes = 0); grpmax FAF= 0.00017932.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 9.98524e-05; MAF= 0.00999%, 28/280414 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000203669; MAF= 0.02037%, 26/127658 alleles, homozygotes = 0); grpmax FAF= 0.00014731.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 PP3 requires multiple lines of computational evidence supporting a deleterious effect. SpliceAI max delta score is 0.10, which does not predict a significant splicing impact (threshold ≥0.2). REVEL and BayesDel scores are unavailable as the variant is intronic. No in silico tool supports a damaging prediction. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.10 — below the 0.2 threshold for predicted splice impact
- REVEL and BayesDel not applicable to intronic variants
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. SpliceAI max delta score of 0.10 does not predict a significant splicing alteration, consistent with a benign interpretation. However, ACMG/AMP guidance requires multiple independent lines of computational evidence; SpliceAI is the sole applicable in silico predictor for this intronic variant, and REVEL/BayesDel/HCI are unavailable. A single computational predictor does not meet the multiple-lines requirement for BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.10 — no predicted splice impact
- Only one computational line available
- BP4 requires multiple lines
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_000368.5:c.1438+6G>A is intronic, not synonymous. While SpliceAI predicts no splicing impact (delta 0.10), BP7 criteria are explicitly defined for synonymous coding variants and are not directly applicable to intronic variants. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
9 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
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PMID 25741868 ↗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. · 2015No paper-specific finding is recorded.
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
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PMID 20301399 ↗Tuberous Sclerosis Complex.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 23519317 ↗Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.Schaefer GB et al. · 2013No paper-specific finding is recorded.
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PMID 23788249 ↗ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.Green RC et al. · 2013No paper-specific finding is recorded.
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PMID 25356965 ↗ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.ACMG Board of Directors · 2015No paper-specific finding is recorded.
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No paper-specific finding is recorded.
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PMID 27854360 ↗Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.Kalia SS et al. · 2017No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
243 / 1,611,274 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.100
Open source ↗
ClinVar
7 Likely benign · 3 Benign · 1 Likely Benign · 1 Uncertain significance · 1 benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/48782/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-135782112-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-132906725-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000368.5%3Ac.1438…
- OncoKB ↗www.oncokb.org/gene/TSC1/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=TSC1+c.1438+6G%3EA
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000150812; MAF= 0.01508%, 243/1611274 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000200343; MAF= 0.02003%, 236/1177978 alleles, homozygotes = 0); grpmax FAF= 0.00017932.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 9.98524e-05; MAF= 0.00999%, 28/280414 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000203669; MAF= 0.02037%, 26/127658 alleles, homozygotes = 0); grpmax FAF= 0.00014731.
ClinVar
This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (3 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as benign (1 clinical laboratory). (ClinVarID = 48782)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).