Variant classification summary

NM_000368.5:c.163C>T

TSC1 · NP_000359.1:p.(Gln55Ter) · NM_000368.5

GRCh37: chr9:135802635 G>A · GRCh38: chr9:132927248 G>A

Gene: TSC1 Transcript: NM_000368.5

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

TSC1

Transcript

NM_000368.5

Protein

NP_000359.1:p.(Gln55Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): nonsense variant p.(Gln55Ter) in exon 4 of 23 is predicted to trigger nonsense-mediated decay, removing about 95% of the 1164-amino-acid protein; germline loss-of-function is an established TSC1 disease mechanism.

2

PM2 (Moderate): the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

3

Synthesis: PVS1 (Very Strong) + PM2 (Moderate) maps to Likely Pathogenic under the generic ACMG/AMP 2015 combination rules.

Final determination: Generic ACMG/AMP 2015 combination rule: 1 Very Strong (PVS1) + 1 Moderate (PM2) = Likely Pathogenic.

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	Met	Met (Very Strong): nonsense change p.(Gln55Ter) in exon 4 of 23 is predicted to trigger nonsense-mediated decay, removing about 95% of the protein.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework PMID:10227394
PS1	N/A	Not applicable: as a nonsense variant, no altered amino acid exists to compare against a previously established pathogenic change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented de novo occurrence with both parents tested and biological parentage confirmed.
PS3	Not assessed	Not assessed: no validated functional assay data testing this exact variant was available.
PS4	Not assessed	Not assessed: no case-control or enrichment dataset for this exact variant was available.	clinvar
PM1	N/A	Not applicable: PM1 applies to missense variants in hotspots; this nonsense change leaves no altered residue to evaluate.	generic_acmg_combination_rules
PM2	Met	Met (Moderate): the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	N/A	Not applicable: TSC1-related disease is autosomal dominant, and no second pathogenic allele in trans was observed.	PMID:17304050
PM4	N/A	Not applicable: the variant causes no change in protein length, so this length-change criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense change at the residue; this nonsense variant produces no missense change.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: the de novo claim lacks parental test results, phenotype, and parentage documentation.
PP1	Not assessed	Not assessed: no family segregation or pedigree data was available for this variant.
PP2	N/A	Not applicable: PP2 applies to missense variants; no missense change is present to evaluate.	generic_acmg_combination_rules
PP3	N/A	Not applicable: SpliceAI maximum delta score 0.005 shows no predicted splice disruption, and in-silico missense paths do not apply to nonsense variants.	spliceai
PP4	Not assessed	Not assessed: no proband phenotype documenting features specific to a TSC1-related disorder was provided.	clinvar
PP5	Not assessed	Not assessed: ClinVar contains laboratory pathogenic submissions but no expert-panel assertion for this variant.	clinvar
BA1	Not met	Not met: the variant is absent from population databases, so no allele frequency approaches the stand-alone benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from all three population datasets, so no allele frequency exceeds the expected benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no observation of the variant in a healthy adult, including no homozygote, was available.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay showing normal protein function for this exact variant was available.
BS4	Not assessed	Not assessed: no non-segregation observation, such as an affected relative lacking the variant, was available.
BP1	N/A	Not applicable: BP1 applies to missense variants; this is a truncating change in a gene where truncation causes disease.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phase data with a second pathogenic variant was available.	PMID:17304050
BP3	N/A	Not applicable: BP3 applies to in-frame indels in repeat regions; this variant does not alter protein length.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: the variant's predicted consequence is protein truncation, not a benign no-impact change.	spliceai
BP5	Not assessed	Not assessed: no alternative molecular diagnosis explaining the phenotype was provided.	clinvar
BP6	Not assessed	Not assessed: no ClinVar expert-panel benign assertion exists for this variant.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants; this nonsense change alters the encoded protein.	generic_acmg_combination_rules

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.