Variant classification summary

NM_000368.5:c.2865C>T

TSC1 · NP_000359.1:p.(Thr955=) · NM_000368.5

GRCh37: chr9:135772681 G>A · GRCh38: chr9:132897294 G>A

Gene: TSC1 Transcript: NM_000368.5

Final call

Benign

BS1 strong BS2 strong

Variant details

Gene

TSC1

Transcript

NM_000368.5

Protein

NP_000359.1:p.(Thr955=)

gnomAD AF

0.0025251617875370006 (v4.1)

ClinVar

Benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BS1 (Strong): allele frequency ~0.3% in gnomAD exceeds the ~0.006% maximum credible TSC1 disease-allele frequency by ~40-50x.

2

BS2 (Strong): 10 homozygotes in gnomAD v4.1 for a fully penetrant, early-onset autosomal dominant disorder.

3

Benign: two strong benign criteria (BS1 + BS2) under the generic ACMG/AMP 2015 combination rule.

Final determination: Under the generic ACMG/AMP 2015 fallback combination rules (no TSC1 VCEP/CSPEC exists), the presence of two strong benign criteria (BS1 + BS2) classifies the variant as Benign (rule: 2 BS -> Benign), with BA1 not met and no pathogenic-supporting criterion applied.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: the variant is synonymous (p.Thr955=), so no null-variant mechanism such as nonsense-mediated decay is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: as a synonymous change (p.Thr955=), no altered amino acid exists to compare against a known pathogenic variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no de novo occurrence with confirmed parentage is reported for this variant.	PMID:15798777 clinvar
PS3	Not assessed	Not assessed: no well-established functional study of this variant was available.	PMID:25741868 spliceai
PS4	Not met	Not met: the variant is a common polymorphism (gnomAD AF 0.17-0.25%) with no case-control enrichment evidence.	PMID:10533067 PMID:15798777 gnomad_v2 gnomad_v4
PM1	N/A	Not applicable: the synonymous change leaves no altered residue to evaluate for a mutational hotspot.	generic_acmg_combination_rules
PM2	Not met	Not met: allele frequency 0.25% (gnomAD v4.1) far exceeds the 0.1% rarity threshold.	gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules PMID:25741868
PM3	N/A	Not applicable: TSC is autosomal dominant, so recessive trans-phase evidence cannot apply.	PMID:25741868 PMID:15798777 PMID:10533067
PM4	N/A	Not applicable: the synonymous change causes no protein length alteration.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change exists at this residue to compare with a different pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo occurrence, with or without confirmed parentage, is reported.	PMID:15798777 clinvar
PP1	Not assessed	Not assessed: no segregation data in affected family members was available.	PMID:10533067 PMID:15798777 clinvar
PP2	N/A	Not applicable: missense-constraint reasoning does not apply to a synonymous change.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.17 is below the 0.20 splice-altering threshold, so no splice impact is predicted.	spliceai PMID:25741868
PP4	Not assessed	Not assessed: no proband phenotype or family-history data was available.
PP5	Not met	Not met: no ClinVar expert panel has classified this variant as pathogenic (aggregate is Benign/Likely benign).	clinvar
BA1	Not met	Not met: highest allele frequency 0.32% (gnomAD v4.1 NFE) is well below the 5% threshold.	gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules PMID:25741868
BS1	Met	Met (Strong): allele frequency ~0.3% exceeds the maximum credible TSC1 disease-allele frequency (~0.006%) by ~40-50x.	gnomad_v4 gnomad_v2 gnomad_canada clinvar generic_acmg_combination_rules PMID:25741868
BS2	Met	Met (Strong): 10 homozygotes in gnomAD v4.1 are incompatible with a fully penetrant, early-onset dominant disorder.	gnomad_v4 gnomad_v2 gnomad_canada clinvar generic_acmg_combination_rules PMID:25741868
BS3	Not assessed	Not assessed: no well-established functional study showing no damaging effect was available.	PMID:25741868 spliceai
BS4	Not assessed	Not assessed: no data on affected relatives lacking the variant was available.	PMID:10533067 clinvar
BP1	N/A	Not applicable: the variant is synonymous, not missense, so this criterion does not apply.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no cis/trans phase data against a pathogenic variant is available.	PMID:25741868 clinvar PMID:10533067
BP3	N/A	Not applicable: the synonymous change causes no in-frame length alteration in a repeat region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: only one independent computational no-impact line (SpliceAI) exists, short of the multiple-line requirement.	spliceai PMID:25741868
BP5	Not assessed	Not assessed: no case-level data showing an alternative molecular cause in a carrier was available.
BP6	Not met	Not met: the ClinVar benign label comes from routine laboratory submissions, not an expert panel.	clinvar
BP7	Not assessed	Not assessed: conservation data (phyloP/GERP) was unavailable to complete the synonymous/splice-neutral check; flagged for human review.	spliceai PMID:25741868

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.