About MTOR
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MTOR c.3610A>G, p.(Ile1204Val)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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 ClinGen MTOR VCEP v1.1. 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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_004958.4:c.3610A>G is absent from all population databases (gnomAD v2.1, gnomAD v4.1, gnomAD-Canada v1.0). Under the Brain Malformations CSPEC v1.1, PM2 is applied at supporting strength for variants absent/rare from controls in an ethnically-matched cohort population sample.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen Brain Malformations Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.1 v1.1 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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. MTOR, an intracellular kinase that regulates cell growth and metabolism, is infrequently mutated in various cancer types.
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
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MTOR VCEP v1.1, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 13 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_004958.4:c.3610A>G (p.Ile1204Val) is a missense variant in the MTOR gene, which is associated with cerebral malformation via a gain-of-function mechanism (Brain Malformations CSPEC v1.1).
This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength under the Brain Malformations CSPEC.
No pathogenic or benign classifications exist in ClinVar; the variant has not been reported in any clinical or research database.
No functional studies, case reports, de novo observations, or segregation data are available for this variant. OncoKB classifies the variant as Unknown Oncogenic Effect.
The CSPEC framework marks 13 criteria as not applicable for MTOR variant assessment: PVS1 (GOF mechanism), PM6 (addressed under PS2), PP1 (mosaic/de novo), PP3 (LOF-focused algorithms), PP4 (accounted under PS4), PP5 (SVI recommendation), BS4 (de novo/mosaic), BP1 (LOF not mechanism), BP4 and BP7 (not applicable to missense), BP6 (SVI recommendation).
With only one supporting-level pathogenic criterion (PM2_supporting) met and no benign criteria met, this variant is classified as a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 combination rules.
No criteria match.
Met · 1
PM2 SupportingNM_004958.4:c.3610A>G is absent from all population databases (gnomAD v2.1, gnomAD v4.1, gnomAD-Canada v1.0). Under the Brain Malformations CSPEC v1.1, PM2 is applied at supporting strength for variants absent/rare from controls in an ethnically-matched cohort population sample. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0 (genomes).
Sources
Not met · 13 · evaluated, threshold not reached
PS1 No different nucleotide change at codon 1204 that produces the same p.Ile1204Val amino acid change has been established as pathogenic. The variant is absent from ClinVar entirely with no submissions at this residue. Details ▾Hide ▴
Evidence considered
- ClinVar has no entries for any variant at codon 1204 of MTOR
- no established pathogenic comparator from a different nucleotide change exists.
Sources
PS2 No de novo observation has been reported for NM_004958.4:c.3610A>G. The CSPEC requires evidence of somatic mosaicism (detectable allele fraction in affected tissue absent from parental samples) for PS2_strong, or confirmed de novo for PS2_moderate. Neither criterion is met. Details ▾Hide ▴
Evidence considered
- No de novo or somatic mosaic evidence identified for this variant in any source.
Still missing
- No patient case reports or de novo sequencing data available for this variant.
PS3 No well-established in vitro or in vivo functional studies have been identified for p.Ile1204Val. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional evidence. No published literature with functional characterization of this variant was identified. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect — no variant-specific reviewed functional evidence available.
- No PMIDs with variant-specific functional data identified.
Still missing
- No functional study has tested this specific variant or a systematically characterized range that includes position 1204.
Sources
PS4 No affected individuals harboring NM_004958.4:c.3610A>G have been reported in the literature or clinical databases (ClinVar, COSMIC). The CSPEC PS4 point system cannot be applied in the absence of any case-level data. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar with zero submissions.
- Variant not reported in COSMIC.
Still missing
- No patient cases or cohort studies reporting this variant.
Sources
PM1 The CSPEC restricts PM1 to supporting-strength for residues affecting critical functional domains as specified in Table 4. Table 4 is not available in the VCEP materials for review. Additionally, p.Ile1204 is not located in a statistically significant hotspot per cancerhotspots.org, and the residue lies in a region of MTOR outside the kinase domain (residues ~2182-2516) that harbors most known pathogenic missense variants. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue 1204 not a statistically significant hotspot.
- CSPEC PM1 requires Table 4 domain reference which is absent from VCEP materials.
Still missing
- Table 4 (critical functional domains) from the CSPEC supplementary materials is not available in the VCEP directory.
PM5 No pathogenic missense variant at amino acid residue 1204 of MTOR has been identified in ClinVar or the literature. The standard PM5 criterion requires a different amino acid change at the same residue to be established as pathogenic, which is not available for this variant. Details ▾Hide ▴
Evidence considered
- ClinVar contains no pathogenic variants at MTOR residue 1204.
- PM5 candidate search returned zero same-residue candidates.
Sources
clinvar ↗pm5_candidates
PP2 The CSPEC awards PP2 at supporting strength when the gnomAD missense constraint z-score exceeds 3.09 for MTOR. The missense z-score was not available in the evidence packet. Without this metric, the criterion cannot be met. Details ▾Hide ▴
Evidence considered
- gnomAD missense constraint z-score for MTOR not available in evidence packet.
Still missing
- gnomAD missense constraint z-score for MTOR needs to be retrieved and compared to the CSPEC threshold of >3.09.
BA1 Under the Brain Malformations CSPEC v1.1, BA1 requires an allele frequency greater than 0.0926%. NM_004958.4:c.3610A>G is absent from all gnomAD populations (v2.1, v4.1, Canada) with an observed allele frequency of 0. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF = 0).
- gnomAD v4.1: absent (AF = 0).
- gnomAD-Canada: absent (AF = 0).
- CSPEC BA1 threshold: >0.0926% — not met.
Sources
BS1 Under the Brain Malformations CSPEC v1.1, BS1 requires an allele frequency greater than 0.0185%. NM_004958.4:c.3610A>G is absent from all gnomAD populations (v2.1, v4.1, Canada) with an observed allele frequency of 0. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF = 0).
- gnomAD v4.1: absent (AF = 0).
- gnomAD-Canada: absent (AF = 0).
- CSPEC BS1 threshold: >0.0185% — not met.
Sources
BS2 The CSPEC awards BS2 if ≥3 homozygotes are present in gnomAD or ≥3 heterozygous individuals are observed in well-phenotyped family members. NM_004958.4:c.3610A>G is absent from all gnomAD populations; no homozygous individuals exist. No well-phenotyped heterozygous family member data is available. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: zero homozygotes.
- gnomAD v4.1: zero homozygotes.
- No well-phenotyped heterozygous family member data available.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect on MTOR protein function have been identified for p.Ile1204Val. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional data available. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect — no variant-specific functional evidence for benign effect.
- No published functional studies showing normal protein function for this variant.
Still missing
- No functional studies have tested this variant for a benign or neutral effect.
Sources
BP2 No evidence that NM_004958.4:c.3610A>G has been observed in cis or trans with a known pathogenic variant in MTOR. Details ▾Hide ▴
Evidence considered
- No cis/trans phase data available for this variant with any pathogenic MTOR variant.
Still missing
- No phase information available from clinical or research testing.
BP5 No evidence exists that NM_004958.4:c.3610A>G has been observed in a case with an alternate molecular basis for disease. No clinical case data is available for this variant. Details ▾Hide ▴
Evidence considered
- No case reports or clinical data identify an alternate molecular basis for disease in a carrier of this variant.
Still missing
- No patient phenotype data available.
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThe Brain Malformations CSPEC (v1.1) explicitly marks PVS1 as not applicable for MTOR. Loss of function and haploinsufficiency have not been established as disease mechanisms; the disease mechanism for MTOR is gain of function (GOF). This variant is a missense substitution (p.Ile1204Val) and would not qualify under the generic PVS1 framework regardless. Details ▾Hide ▴
Evidence considered
- CSPEC v1.1 explicitly designates PVS1 as not applicable for MTOR
- GOF disease mechanism confirmed.
- PVS1 variant assessment classifies this as 'other' bucket — not a null variant eligible for generic PVS1.
Sources
PM6 VCEPThe Brain Malformations CSPEC v1.1 explicitly marks PM6 as not applicable. Assumed de novo without confirmation of paternity and maternity is addressed under the modified PS2 criterion. Details ▾Hide ▴
Evidence considered
- CSPEC v1.1: PM6 not applicable for this VCEP
- addressed according to PS2.
Sources
PP1 VCEPThe Brain Malformations CSPEC v1.1 explicitly marks PP1 as not applicable. Disease-causing variants are germline mosaic, de novo, or mosaic, making co-segregation analysis infeasible. Details ▾Hide ▴
Evidence considered
- CSPEC v1.1: PP1 not applicable since disease-causing variants are germline mosaic
- de novo or mosaic.
Sources
PP3 VCEPThe Brain Malformations CSPEC v1.1 explicitly marks PP3 as not applicable. Traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms, whereas MTOR variants act through gain of function. The REVEL score (0.186) and BayesDel score (-0.200856) are not considered applicable under this CSPEC. Details ▾Hide ▴
Evidence considered
- CSPEC v1.1: PP3 not applicable — prediction algorithms focus on LOF
- not GOF.
- REVEL score 0.186
- BayesDel score -0.200856 (not evaluated per CSPEC exclusion).
Sources
PP4 VCEPThe Brain Malformations CSPEC v1.1 explicitly marks PP4 as not applicable. The phenotype specificity criterion is accounted for under the CSPEC's modified PS4 scoring system. Details ▾Hide ▴
Evidence considered
- CSPEC v1.1: PP4 not applicable since this criterion is accounted for under PS4.
Sources
PP5 VCEPThe Brain Malformations CSPEC v1.1 explicitly marks PP5 as not applicable per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Additionally, the variant is absent from ClinVar, so no reputable source classification exists to consider. Details ▾Hide ▴
BS4 VCEPThe Brain Malformations CSPEC v1.1 explicitly marks BS4 as not applicable. Lack of segregation analysis is not applicable since these are de novo, germline mosaic, or post-zygotic mutations. Details ▾Hide ▴
Evidence considered
- CSPEC v1.1: BS4 not applicable — disease-causing variants are de novo
- germline mosaic or post-zygotic.
Sources
BP1 VCEPThe Brain Malformations CSPEC v1.1 explicitly marks BP1 as not applicable. Missense variants in MTOR are not subject to BP1 since loss of function is not the disease mechanism. Details ▾Hide ▴
Evidence considered
- CSPEC v1.1: BP1 not applicable as LOF is not the disease mechanism.
Sources
BP4 N/AThe Brain Malformations CSPEC v1.1 restricts BP4 to synonymous, intronic (except canonical splice sites), and non-coding UTR variants. NM_004958.4:c.3610A>G is a missense variant (p.Ile1204Val) and is not eligible for BP4 under this specification. Details ▾Hide ▴
Evidence considered
- CSPEC v1.1: BP4 applicable only for synonymous/intronic/UTR variants
- this is a missense variant.
Sources
BP6 VCEPThe Brain Malformations CSPEC v1.1 explicitly marks BP6 as not applicable per the ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Evidence considered
- CSPEC v1.1: BP6 not for use per ClinGen SVI VCEP Review Committee.
Sources
BP7 N/AThe Brain Malformations CSPEC v1.1 restricts BP7 to synonymous, intronic (except canonical splice sites), and non-coding UTR variants with PhyloP score <0.1. NM_004958.4:c.3610A>G is a missense variant (p.Ile1204Val) and is not eligible for BP7 under this specification. Details ▾Hide ▴
Evidence considered
- CSPEC v1.1: BP7 applicable only for synonymous/intronic/UTR variants
- this is a missense variant.
Sources
PS5 N/APS5 is not a recognized ACMG/AMP criterion. The standard pathogenic criteria are PVS1 and PS1 through PS4. PS5 does not exist in either the generic ACMG/AMP 2015 framework (PMID:25741868) or the Brain Malformations CSPEC v1.1. Details ▾Hide ▴
Evidence considered
- PS5 is not defined in the ACMG/AMP framework.
Identifiers
- Gene
- MTOR
- Transcript
- NM_004958.4
- Coding (HGVS c.)
- NM_004958.4:c.3610A>G
- Protein (HGVS p.)
- NP_004949.1:p.(Ile1204Val)
- GRCh38
- chr1:11210858 T>C
- GRCh37
- chr1:11270915 T>C
Gene diagram
Every interpreted variant in MTOR, mapped onto the exon structure of NM_004958.4. Select a row to find it on the plot.
MTORNM_004958.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MTOR
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.186
- BayesDel
- -0.201
How the predictions were used
PP3 VCEPThe Brain Malformations CSPEC v1.1 explicitly marks PP3 as not applicable. Traditional mutation pathogenicity prediction algorithms focus on loss-of-function mechanisms, whereas MTOR variants act through gain of function. The REVEL score (0.186) and BayesDel score (-0.200856) are not considered applicable under this CSPEC. Details ▾Hide ▴
Evidence considered
- CSPEC v1.1: PP3 not applicable — prediction algorithms focus on LOF
- not GOF.
- REVEL score 0.186
- BayesDel score -0.200856 (not evaluated per CSPEC exclusion).
Sources
BP4 N/AThe Brain Malformations CSPEC v1.1 restricts BP4 to synonymous, intronic (except canonical splice sites), and non-coding UTR variants. NM_004958.4:c.3610A>G is a missense variant (p.Ile1204Val) and is not eligible for BP4 under this specification. Details ▾Hide ▴
Evidence considered
- CSPEC v1.1: BP4 applicable only for synonymous/intronic/UTR variants
- this is a missense variant.
Sources
BP7 N/AThe Brain Malformations CSPEC v1.1 restricts BP7 to synonymous, intronic (except canonical splice sites), and non-coding UTR variants with PhyloP score <0.1. NM_004958.4:c.3610A>G is a missense variant (p.Ile1204Val) and is not eligible for BP7 under this specification. Details ▾Hide ▴
Evidence considered
- CSPEC v1.1: BP7 applicable only for synonymous/intronic/UTR variants
- this is a missense variant.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.186. BayesDel score = -0.200856.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
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 ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/467907148
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_004958.4%3Ac.3610A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-11270915-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-11210858-T-C?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-11210858-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_004958.4%3Ac.3610…
- OncoKB ↗www.oncokb.org/gene/MTOR/I1204V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MTOR+c.3610A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.186. BayesDel score = -0.200856.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MTOR, an intracellular kinase that regulates cell growth and metabolism, is infrequently mutated in various cancer types.
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.