NM_000368.4:c.3106G>A

TSC1 · NP_000359.1:p.(Gly1036Arg) · NM_000368.4

GRCh37: chr9:135772011 C>T · GRCh38: chr9:132896624 C>T

Gene: TSC1 Transcript: NM_000368.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

TSC1

Transcript

NM_000368.4

Protein

NP_000359.1:p.(Gly1036Arg)

gnomAD AF

6.196669909590586e-07 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (supporting): This variant is extremely rare in population databases — absent from gnomAD v2.1, present in gnomAD v4.1 at an allele frequency of 6.2e-7 (1/1,613,770 alleles, no homozygotes), and absent from gnomAD-Canada.

BP4 (supporting): Two in silico predictors suggest no deleterious impact — BayesDel score -0.172 (benign) and SpliceAI max delta 0.00 (no splice alteration). REVEL score 0.291 is indeterminate and does not override.

PM2 (supporting) and BP4 (supporting) cancel each other, yielding no net evidence for or against pathogenicity. The variant remains a Variant of Uncertain Significance.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Missense variant (p.Gly1036Arg); does not meet criteria for a null variant (nonsense, frameshift, or canonical ±1,2 splice site). PVS1 variant assessment confirms generic PVS1 framework is not applicable for this variant class.	pvs1_generic_framework pvs1_variant_assessment pvs1_gene_context
PS1	Not met	No known pathogenic variant at codon 1036 with a different nucleotide change producing the same amino acid change (p.Gly1036Arg). No comparator variants identified that would satisfy PS1.	pm5_candidates
PS2	Not met	No de novo observation with confirmed maternity and paternity identified for this variant in the reviewed literature.
PS3	Not met	No variant-specific functional studies identified. OncoKB reports Unknown Oncogenic Effect with no supporting functional evidence. No literature describing experimental characterization of c.3106G>A or a systematically characterized range that includes codon 1036.	oncokb
PS4	Not met	No case-control studies or cohort data demonstrating statistically significant enrichment of this variant in affected individuals relative to controls. Reviewed papers are guideline/policy documents, not variant-specific clinical cohorts.
PS5	Not met	No ClinVar pathogenic or likely pathogenic classification for a different nucleotide change at codon 1036 producing the same amino acid change (p.Gly1036Arg). PM5 candidate search returned no comparator variants at this residue.	pm5_candidates clinvar
PM1	Not met	Not located in a statistically significant mutational hotspot per cancerhotspots.org. No domain-level functional evidence specifically implicating the region surrounding codon 1036 was identified in the reviewed literature.
PM2	Met	This variant is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and present in gnomAD v4.1 at an allele frequency of 6.2e-7 (1/1,613,770 alleles, 0 homozygotes), well below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No same-residue comparator variant identified. PM5 candidate search returned zero candidates; unable to confirm a different pathogenic missense change at codon 1036.	pm5_candidates clinvar
PM6	Not met	No de novo observation reported for this variant in the reviewed literature. No family studies with parental testing available.
PP1	Not met	No co-segregation data available. No family studies demonstrating segregation of this variant with disease phenotype.
PP2	Not met	Insufficient data to determine whether TSC1 has a low rate of benign missense variation and whether missense variants are a common disease mechanism. TSC1 missense Z-score and constraint metrics were not available in the evidence packet.
PP3	Not met	Multiple in silico tools do not support a deleterious effect: REVEL score 0.291 is in the indeterminate range (neither benign <0.25 nor pathogenic >0.5), BayesDel score -0.172 is in the benign range (<0.0), and SpliceAI max delta 0.00 predicts no splice impact.	revel bayesdel spliceai
PP4	Not met	No patient-specific clinical phenotype or family history data provided for this variant. Cannot assess whether the clinical presentation is highly specific for TSC1-related disease.
PP5	Not met	ClinVar classification for this variant is Uncertain Significance (3 submitters) with review status 'criteria provided, single submitter' (1-star). Does not meet the 3-star expert panel threshold required for PP5 at any strength under the generic ACMG framework.	clinvar
BA1	Not met	Allele frequency in gnomAD v4.1 is 6.2e-7 (0.00006%), well below the 1% BA1 threshold. Absent from gnomAD v2.1 and gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Allele frequency in gnomAD v4.1 is 6.2e-7 (0.00006%), well below the 0.3% BS1 threshold. Highest subpopulation frequency (African/African American) is 1.3e-5 (0.00133%), also well below threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Only 1 allele observed among >1.6 million alleles in gnomAD v4.1, with 0 homozygotes. This single observation is insufficient to establish that the variant occurs in healthy adults at a frequency supporting a benign interpretation under BS2.	gnomad_v4
BS3	Not met	No variant-specific functional studies demonstrating a benign effect. No experimental evidence characterizing the functional impact of p.Gly1036Arg.	oncokb
BS4	Not met	No non-segregation data available. No family studies demonstrating absence of the variant in affected relatives or presence in unaffected relatives.
BP1	Not met	While truncating variants in TSC1 cause tuberous sclerosis complex, missense variants are also a recognized disease mechanism in TSC1 (e.g., disrupting the TSC1-TSC2 interaction). TSC1 is not a gene where disease is caused exclusively or primarily by truncating variants; pathogenic missense variants are well-documented.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic TSC1 variant. No data available to support BP2.
PM3	N/A	PM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant; TSC1 is an autosomal dominant disorder.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants; this is a missense substitution.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution.
BP4	Met	Two independent in silico predictors suggest no deleterious impact: BayesDel score -0.172 is in the benign range (<0.0) and SpliceAI max delta 0.00 predicts no splice alteration. REVEL score 0.291 falls in the indeterminate range but does not contradict the benign predictions.	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease. No data available to support BP5.
BP6	Not met	ClinVar classification for this variant is Uncertain Significance (3 submitters), not benign or likely benign. The 1-star review status does not support BP6 application.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact; this is a missense variant (c.3106G>A, p.Gly1036Arg).

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