NM_000368.4:c.1022C>T

TSC1 · NP_000359.1:p.(Pro341Leu) · NM_000368.4

GRCh37: chr9:135786847 G>A · GRCh38: chr9:132911460 G>A

Gene: TSC1 Transcript: NM_000368.4

Final call

Likely Benign

PM2 supporting BS2 supporting BP4 supporting

Variant details

Gene

TSC1

Transcript

NM_000368.4

Protein

NP_000359.1:p.(Pro341Leu)

gnomAD AF

6.207894952484772e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (supporting): This variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at extremely low frequency (AF=0.000062%, 10/1,610,852 alleles, 0 homozygotes), well below the PM2 threshold of less than 0.1%.

BS2 (supporting): This variant is observed in 10 heterozygous individuals in gnomAD v4.1. TSC is a dominant disorder with near-complete penetrance and early childhood onset; observation in a population database of presumably healthy adults is inconsistent with a fully penetrant pathogenic variant.

BP4 (supporting): BayesDel score 0.161 is in the benign range. REVEL score 0.496 is borderline (just below 0.5 pathogenic threshold). SpliceAI max delta 0.02 predicts no splicing impact. Multiple computational lines of evidence suggest no deleterious effect.

PVS1 not applicable: Variant is a missense substitution (p.Pro341Leu), not a null variant eligible for PVS1 assessment.

PM1 not met: This variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org.

PM5 not met: No same-residue pathogenic missense comparator variants were identified.

PS3 not met: No functional studies have been reported for this variant. OncoKB reports Unknown Oncogenic Effect.

PP3 not met: REVEL 0.496 is borderline; BayesDel 0.161 is benign; SpliceAI max delta 0.02 shows no splice impact. In silico tools do not converge on a damaging prediction.

PP5 not met: ClinVar review status is 1-star (criteria provided, single submitter), not 3-star expert panel. Classification is Uncertain significance with mixed submitters.

BP6 not met: ClinVar review status is 1-star, not 3-star expert panel. A single submitter classifies as Benign, insufficient for BP6.

No publications reviewed contained variant-specific evidence for NM_000368.4:c.1022C>T. All PMIDs are guideline/review papers that do not mention this variant.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	Variant is a missense substitution (p.Pro341Leu), not a null variant (nonsense, frameshift, or canonical splice). The generic PVS1 framework does not apply to missense variants.	pvs1_variant_assessment
PS1	N/A	No other nucleotide change at the same position has been reported as pathogenic to produce the same amino acid change (Pro341Leu).
PS2	Not met	No de novo occurrence (maternity and paternity confirmed) has been reported for this variant.
PS3	Not met	No functional studies have been reported for this variant. OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. No publication describes experimental characterization of NM_000368.4:c.1022C>T or a systematically characterized range that includes this position.	oncokb
PS4	Not met	No case-control or cohort data demonstrate enrichment of this variant in affected individuals. No clinical case reports describe this variant in affected probands with TSC.	clinvar gnomad_v4
PS5	N/A	Not a standard ACMG/AMP 2015 criterion. No applicable evidence identified.
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org. Position 341 is not annotated within a well-characterized critical functional domain with absence of benign variation.
PM2	Met	This variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at extremely low frequency (AF=0.000062%, 10/1,610,852 alleles, 0 homozygotes), well below the PM2 threshold of less than 0.1%.	gnomad_v2 gnomad_v4
PM5	Not met	No same-residue pathogenic missense comparator variants were identified in automated PM5 candidate harvesting.	pm5_candidates
PM6	Not met	No de novo observation (maternity and paternity unconfirmed) has been reported for this variant.
PP1	Not met	No co-segregation data available. No family studies have been reported for this variant.
PP2	Not met	No missense constraint data (z-score) was available to confirm TSC1 has a low rate of benign missense variation where missense is a common disease mechanism.
PP3	Not met	REVEL score 0.496 is borderline/equivocal, BayesDel score 0.161 is in the benign range, and SpliceAI max delta is 0.02 (no splice impact). Multiple in silico tools do not converge on a damaging prediction.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history information was provided for assessment of phenotypic specificity.
PP5	Not met	ClinVar review status is 'criteria provided, single submitter' (1-star), not 3-star expert panel. Classification is uncertain significance with 3 submitters and benign with 1 submitter. PP5 requires a 3-star expert panel classification as Pathogenic/Likely Pathogenic.	clinvar
BA1	Not met	gnomAD v4.1 allele frequency is 0.000062%, far below the BA1 threshold of greater than 1%.	gnomad_v4
BS1	Not met	gnomAD v4.1 allele frequency is 0.000062%, below the BS1 threshold of greater than 0.3%.	gnomad_v4
BS2	Met	This variant is observed in 10 heterozygous individuals in gnomAD v4.1 (0 homozygotes). TSC is a dominant disorder with near-complete penetrance and early childhood onset. Observation in a population database of presumably healthy adults is inconsistent with a fully penetrant pathogenic variant, supporting a benign interpretation.	gnomad_v4
BS3	Not met	No functional studies demonstrating no deleterious effect have been reported for this variant. OncoKB reports Unknown Oncogenic Effect.	oncokb
BS4	Not met	No non-segregation data available for this variant.
BP1	Not met	Although TSC1 loss of function is a known disease mechanism, both truncating and missense pathogenic variants are well-documented in TSC1. The variant spectrum does not support that primarily truncating variants cause disease to the exclusion of missense.	pvs1_gene_context
BP2	Not met	No observation in trans with a pathogenic variant has been reported for this dominant disorder.
BP4	Met	BayesDel score 0.161 is in the benign range (threshold greater than 0.27 for pathogenic). REVEL score 0.496 is borderline, just below the 0.5 pathogenic threshold. SpliceAI max delta 0.02 predicts no splicing impact. Multiple computational lines of evidence suggest no deleterious effect.	revel bayesdel spliceai
BP5	Not met	No alternative molecular basis for disease has been identified that would explain the phenotype independent of this variant.
BP6	Not met	ClinVar review status is 'criteria provided, single submitter' (1-star), not 3-star expert panel. A single submitter classified as Benign. BP6 requires a 3-star expert panel classification as Benign/Likely Benign.	clinvar
BP7	N/A	Variant is a missense substitution (c.1022C>T, p.Pro341Leu), not a synonymous/silent variant. BP7 applies only to synonymous variants without predicted splice impact.

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.