TSC1c.3106G>AUncertain significance

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Variant interpretation report

TSC1 c.3106G>A, p.(Gly1036Arg)

NM_000368.4:c.3106G>A NP_000359.1:p.(Gly1036Arg) View identifiers

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.

About TSC1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 supporting (benign) · 1 supporting (pathogenic)
Expert rules: Not recorded
Other laboratories (ClinVar): 2 Uncertain significance · 1 Uncertain Significance
Pipeline record: 21 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): 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.
BP4 (supporting): 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.

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

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.

Benign criteria applied · 1

BP4Supporting

BP4 · supporting

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.

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, BP4 supporting; 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

1 / 1,613,770 alleles

gnomAD v4.1: 1 / 1,613,770 alleles. Recorded AF 6.19667e-07. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗

ClinVar submissions

3 reported laboratory submissions

2 Uncertain significance · 1 Uncertain Significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. TSC1, a scaffold protein, is frequently altered by mutation in bladder cancer.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

Met · 2

PM2 SupportingThis 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent
gnomAD v4.1: AF = 6.2e-7 (1/1
613
770 alleles
0 homozygotes)
gnomAD-Canada v1.0: absent

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP4 SupportingTwo 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. Details ▾Hide ▴

Evidence considered

BayesDel: -0.172 (benign)
SpliceAI: max delta = 0.00 (no splicing impact predicted)
REVEL: 0.291 (indeterminate
does not contradict benign findings)

Sources

revelbayesdelspliceai ↗

Not met · 22 · evaluated, threshold not reached

PS1 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. Details ▾Hide ▴

Evidence considered

PM5 candidate search found zero same-residue variants
no alternative nucleotide change at c.3106 producing G1036R identified

Sources

pm5_candidates

PS2 No de novo observation with confirmed maternity and paternity identified for this variant in the reviewed literature. Details ▾Hide ▴

Still missing

No de novo testing or family studies available

PS3 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. Details ▾Hide ▴

Evidence considered

OncoKB: Unknown Oncogenic Effect
no PMIDs with functional evidence
No publications with variant-specific experimental functional data

Still missing

No functional characterization of p.Gly1036Arg or a saturation mutagenesis range covering codon 1036

Sources

oncokb ↗

PS4 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. Details ▾Hide ▴

Evidence considered

All reviewed publications are policy/guideline papers with no variant-level patient data
gnomAD population data (1/1.6M alleles) insufficient without matched affected cohort

Still missing

No case-control or cohort enrichment data available

PM1 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. Details ▾Hide ▴

Evidence considered

cancerhotspots.org: residue not significant
exact variant not listed
No domain-specific functional characterization of the p.Gly1036 region in reviewed literature

Still missing

TSC1 C-terminal domain (which includes residue 1036) is known to interact with TSC2
targeted domain-level literature search could be pursued

PM5 No same-residue comparator variant identified. PM5 candidate search returned zero candidates; unable to confirm a different pathogenic missense change at codon 1036. Details ▾Hide ▴

Evidence considered

PM5 candidate search: 0 candidates
same-residue mode unknown
ClinVar VUS (c.3106G>A) is the only variant reported at codon 1036

Sources

pm5_candidatesclinvar ↗

PM6 No de novo observation reported for this variant in the reviewed literature. No family studies with parental testing available. Details ▾Hide ▴

Still missing

No de novo or trios data available

PP1 No co-segregation data available. No family studies demonstrating segregation of this variant with disease phenotype. Details ▾Hide ▴

Still missing

No segregation or family linkage data

PP2 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. Details ▾Hide ▴

Evidence considered

No gene-level missense constraint or Z-score data available in evidence brief

Still missing

TSC1 missense constraint metrics (Z-score
gnomAD missense OE) not provided

PP3 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. Details ▾Hide ▴

Evidence considered

REVEL: 0.291 (indeterminate
between 0.25 and 0.50 thresholds)
BayesDel: -0.172 (benign
below 0.0 threshold)
SpliceAI: max delta = 0.00 (no splice alteration predicted)

Sources

revelbayesdelspliceai ↗

PP4 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. Details ▾Hide ▴

Still missing

No proband clinical phenotype data provided

PP5 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. Details ▾Hide ▴

Evidence considered

ClinVar VCV000663161: Uncertain Significance
review status = criteria provided
single submitter (1-star)
No expert panel submission
3 clinical laboratory submitters all reporting VUS

Sources

clinvar ↗

BA1 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. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 total AF = 6.2e-7
far below 1% BA1 cutoff
gnomAD v2.1: absent
gnomAD-Canada: absent

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 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. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 total AF = 6.2e-7
far below 0.3% BS1 cutoff
Best subpopulation (AFR) AF = 1.3e-5
also far below 0.3%

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS2 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. Details ▾Hide ▴

Evidence considered

gnomAD v4.1: 1 heterozygote in 1
613
770 alleles
0 homozygotes

Still missing

Single allele observation too sparse for BS2 application

Sources

gnomad_v4 ↗

BS3 No variant-specific functional studies demonstrating a benign effect. No experimental evidence characterizing the functional impact of p.Gly1036Arg. Details ▾Hide ▴

Evidence considered

OncoKB: Unknown Oncogenic Effect
no benign functional data
No publications with functional assays of c.3106G>A

Still missing

No functional characterization of p.Gly1036Arg

Sources

oncokb ↗

BS4 No non-segregation data available. No family studies demonstrating absence of the variant in affected relatives or presence in unaffected relatives. Details ▾Hide ▴

Still missing

No segregation or non-segregation data

BP1 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. Details ▾Hide ▴

Evidence considered

TSC1 LOF is supported but both missense and truncating pathogenic variants are documented
BP1 requires the gene to be one where primarily truncating variants cause disease

Sources

pvs1_gene_context

BP2 No observation of this variant in trans with a known pathogenic TSC1 variant. No data available to support BP2. Details ▾Hide ▴

Still missing

No trans-configuration data with a pathogenic variant

BP5 No observation of this variant in a case with an alternate molecular basis for disease. No data available to support BP5. Details ▾Hide ▴

Still missing

No cases with alternate molecular diagnosis identified

BP6 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. Details ▾Hide ▴

Evidence considered

ClinVar VCV000663161: Uncertain Significance
review status = criteria provided
single submitter (1-star)
No submitter classifies this variant as benign or likely benign

Sources

clinvar ↗

PS5 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. Details ▾Hide ▴

Evidence considered

PM5 candidate search: zero same-residue candidates found
ClinVar contains only this variant (c.3106G>A) at codon 1036 classified as VUS

Sources

pm5_candidatesclinvar ↗

Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AMissense 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. Details ▾Hide ▴

Evidence considered

PVS1 variant assessment returned bucket='other'
apply_generic_pvs1_framework=false
Variant type is missense substitution
not a predicted null variant
Gene-level PVS1 gate is eligible (TSC1 LOF mechanism supported)
but variant does not satisfy null-variant criteria

Sources

pvs1_generic_framework ↗pvs1_variant_assessmentpvs1_gene_context

PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant; TSC1 is an autosomal dominant disorder. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; this is a missense variant (c.3106G>A, p.Gly1036Arg). Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: TSC1
Transcript: NM_000368.4
Coding (HGVS c.): NM_000368.4:c.3106G>A
Protein (HGVS p.): NP_000359.1:p.(Gly1036Arg)
GRCh38: chr9:132896624 C>T
GRCh37: chr9:135772011 C>T
ClinVar: 2625215, 663161

Gene diagram

Every interpreted variant in TSC1, mapped onto the exon structure of NM_000368.4. Select a row to find it on the plot.

TSC1NM_000368.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

—

Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in TSC1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 1 / 1,613,770 alleles AF 6.2e-07 · 0 homozygotes

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,613,770 alleles · 0 hom

African/African American1 / 75,018

1.3e-05

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish).

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19667e-07; MAF= 0.00006%, 1/1613770 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33301e-05; MAF= 0.00133%, 1/75018 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.020

Pangolin splice gain

0.040

Other predictors

REVEL: 0.291
BayesDel: -0.172

How the predictions were used

Evidence considered

BayesDel: -0.172 (benign)
SpliceAI: max delta = 0.00 (no splicing impact predicted)
REVEL: 0.291 (indeterminate
does not contradict benign findings)

Sources

revelbayesdelspliceai ↗

Evidence considered

REVEL: 0.291 (indeterminate
between 0.25 and 0.50 thresholds)
BayesDel: -0.172 (benign
below 0.0 threshold)
SpliceAI: max delta = 0.00 (no splice alteration predicted)

Sources

revelbayesdelspliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact; this is a missense variant (c.3106G>A, p.Gly1036Arg). Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.291. BayesDel score = -0.172488.

6 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

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. · 2015

Presents the ACMG/AMP 2015 standards and guidelines for variant interpretation. NM_000368.4:c.3106G>A was not identified in this paper.
Does not name this variant
PMID 25741868 ↗
Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions.

Schaefer GB et al. · 2013

Provides clinical genetics evaluation guidelines for autism spectrum disorders, including tiered testing recommendations. NM_000368.4:c.3106G>A was not identified in this paper.
Does not name this variant
PMID 23519317 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.

Green RC et al. · 2013

ACMG recommendations for reporting incidental findings in clinical exome and genome sequencing. NM_000368.4:c.3106G>A was not identified in this paper.
Does not name this variant
PMID 23788249 ↗
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. · 2015

ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. TSC is listed in syndromic referral tables but NM_000368.4:c.3106G>A was not identified in this paper.
Does not name this variant
PMID 25394175 ↗
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. · 2017

ACMG SF v2.0 recommendations for reporting secondary findings in clinical exome and genome sequencing. NM_000368.4:c.3106G>A was not identified in the abstract.
Does not name this variant
PMID 27854360 ↗
ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG).

Miller DT et al. · 2022

ACMG SF v3.1 list for reporting secondary findings. TSC1 is listed in the recommended gene table (Tuberous Sclerosis Complex) but NM_000368.4:c.3106G>A was not identified in this paper.
Does not name this variant
PMID 35802134 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,613,770 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 2 Uncertain significance · 1 Uncertain Significance Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 663161)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.291. BayesDel score = -0.172488.

Functional

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.