About NF1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NF1 c.8089_8093delinsGTTTT, p.(Phe2697_Ser2698delinsValLeu)
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 NF1 VCEP v1.0.0. 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
This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the PM2 threshold of 0.1% for rarity-based support.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Neurofibromatosis and Schwannomatosis Specification v1.0.0 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.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
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. NF1, a negative regulator of RAS, is inactivated by mutation or deletion in various solid and hematologic malignancies.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen NF1 VCEP v1.0.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 7 not met · 15 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The NF1 c.8089_8093delinsGTTTT (p.(Phe2697_Ser2698delinsValLeu)) variant has not been reported in ClinVar.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.
No variant-specific reviewed functional study was identified for this exact NF1 change.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01; no REVEL or BayesDel result was available in the reviewed files for this protein-altering delins.
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the PM2 threshold of 0.1% for rarity-based support. Details ▾Hide ▴
Not met · 7 · evaluated, threshold not reached
PVS1 NF1 loss of function is an established disease mechanism, but this variant is an in-frame protein-altering delins rather than a nonsense, frameshift, or canonical splice-site variant, and SpliceAI predicts no significant splice impact (max delta score 0.01). Available evidence therefore does not support application of PVS1. Details ▾Hide ▴
Evidence considered
- NF1 loss-of-function mechanism supported
- generic PVS1 scaffold does not place this variant in a null-variant bucket
- SpliceAI max delta score 0.01
Sources
PM1 Available evidence does not show that this variant lies in an established NF1 mutational hotspot or a critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this site, although the hotspot review was flagged for human review. Details ▾Hide ▴
Evidence considered
- no statistically significant hotspot identified
Still missing
- No validated pathogenic clustering data for residues 2697-2698
Sources
PM4 This variant results in an in-frame amino acid substitution-delins, p.(Phe2697_Ser2698delinsValLeu), without a net protein length change, so available evidence does not support PM4. Details ▾Hide ▴
PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01. No additional validated computational predictor result was available to support a damaging effect for this protein-altering delins, so PP3 is not supported. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01
- REVEL and BayesDel not available for this variant in reviewed files
Still missing
- No applicable validated protein-impact predictor result identified for this indel
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the BA1 threshold of 1% and does not support a benign stand-alone classification. Details ▾Hide ▴
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the BS1 threshold of 0.3% and does not support a benign frequency-based interpretation. Details ▾Hide ▴
BP4 SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, but this alone does not establish a benign overall effect for a protein-altering delins. No additional validated benign computational predictor result was available, so BP4 is not supported. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01
- REVEL and BayesDel not available for this variant in reviewed files
Still missing
- No applicable benign protein-impact predictor result identified for this indel
Sources
Not assessed · 15 · no assessment recorded
PS1 No evidence was identified showing that this variant produces the same amino acid change as a previously established pathogenic variant. Details ▾Hide ▴
Evidence considered
- ClinVar search returned no result
Still missing
- No exact amino-acid-level pathogenic comparator was identified.
Sources
PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant. Details ▾Hide ▴
Evidence considered
- no de novo evidence identified in reviewed sources
Still missing
- No parental testing data
- No confirmed maternity/paternity data
- No de novo case report identified
Sources
PS3 No well-established functional study for this exact variant was identified, so functional evidence supporting a damaging effect is not available. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence
Still missing
- No variant-specific functional assay identified
Sources
PS4 No enrichment data, case-control evidence, or count of multiple unrelated affected individuals with this exact variant was identified. Details ▾Hide ▴
Evidence considered
- variant absent from ClinVar
- variant absent from gnomAD
Still missing
- No prevalence or case-control data
- No independent affected case count identified
Sources
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant. Details ▾Hide ▴
Evidence considered
- no de novo evidence identified in reviewed sources
Still missing
- No case-level family testing data
- No de novo report identified
Sources
PP1 No segregation data were identified for this variant, so cosegregation with disease cannot be assessed. Details ▾Hide ▴
Evidence considered
- no segregation evidence identified
Still missing
- No pedigree data
- No affected-relative genotypes
Sources
PP4 No phenotype information was provided that would allow assessment of whether the observed clinical presentation is highly specific for an NF1-related disorder caused by this gene. Details ▾Hide ▴
Evidence considered
- no case-specific phenotype evidence available in reviewed files
Still missing
- No phenotype summary
- No clinical diagnostic features supplied
Sources
PP5 No reputable source classification for this exact variant was identified in the reviewed materials. Details ▾Hide ▴
Evidence considered
- ClinVar search returned no result
Still missing
- No external classified record identified
Sources
BS2 No evidence was identified showing this variant in healthy adults for whom penetrance expectations would argue against pathogenicity. Details ▾Hide ▴
Evidence considered
- variant absent from gnomAD
Still missing
- No healthy carrier data
Sources
BS3 No well-established functional study showing a normal or benign effect for this exact variant was identified. Details ▾Hide ▴
Evidence considered
- no variant-specific reviewed functional evidence identified
Still missing
- No variant-specific benign functional assay identified
Sources
BS4 No family data were identified showing lack of segregation of this variant with disease. Details ▾Hide ▴
Evidence considered
- no non-segregation evidence identified
Still missing
- No family segregation data
Sources
BP2 No phase information or second variant data were identified to assess whether this variant occurs in trans with a pathogenic variant or in cis with another variant. Details ▾Hide ▴
Evidence considered
- no phase-based evidence identified
Still missing
- No phasing data
- No second-variant data
Sources
BP3 No evidence was identified showing that this in-frame change lies within a repetitive region without known function. Details ▾Hide ▴
Evidence considered
- no repeat-region annotation identified in reviewed materials
Still missing
- No repeat-region assessment for this site
Sources
BP5 No evidence was identified for an alternate molecular explanation that would make this variant an incidental finding unrelated to the phenotype. Details ▾Hide ▴
Evidence considered
- no alternate diagnosis evidence identified
Still missing
- No phenotype context
- No alternate molecular diagnosis data
Sources
BP6 No reputable benign classification for this exact variant was identified in the reviewed materials. Details ▾Hide ▴
Evidence considered
- ClinVar search returned no result
Still missing
- No benign external assertion identified
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is not applicable because this criterion is used for recessive disorders and no recessive phase-based evidence is relevant here. Details ▾Hide ▴
PM5 N/APM5 is not applicable because no evidence was identified for a different established pathogenic missense change at the same amino acid residue, and this variant is a two-residue in-frame delins rather than a single-residue missense substitution. Details ▾Hide ▴
PP2 N/APP2 is intended for missense variants in genes with a low rate of benign missense variation, and this variant is a two-residue in-frame delins rather than a missense substitution. Details ▾Hide ▴
BP1 N/ABP1 is a missense-specific criterion and is not applicable to this two-residue in-frame delins. Details ▾Hide ▴
BP7 N/ABP7 is not applicable because this variant is a coding in-frame delins rather than a synonymous or intronic variant. Details ▾Hide ▴
Identifiers
- Gene
- NF1
- Transcript
- NM_000267.3
- Coding (HGVS c.)
- NM_000267.3:c.8089_8093delinsGTTTT
- Protein (HGVS p.)
- NP_000258.1:p.(Phe2697_Ser2698delinsValLeu)
- GRCh38
- chr17:31359007 TTTTC>GTTTT
- GRCh37
- chr17:29686025 TTTTC>GTTTT
Gene diagram
Every interpreted variant in NF1, mapped onto the exon structure of NM_000267.3. Select a row to find it on the plot.
NF1NM_000267.3
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 NF1
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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
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01. No additional validated computational predictor result was available to support a damaging effect for this protein-altering delins, so PP3 is not supported. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01
- REVEL and BayesDel not available for this variant in reviewed files
Still missing
- No applicable validated protein-impact predictor result identified for this indel
Sources
BP4 SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, but this alone does not establish a benign overall effect for a protein-altering delins. No additional validated benign computational predictor result was available, so BP4 is not supported. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01
- REVEL and BayesDel not available for this variant in reviewed files
Still missing
- No applicable benign protein-impact predictor result identified for this indel
Sources
BP7 N/ABP7 is not applicable because this variant is a coding in-frame delins rather than a synonymous or intronic variant. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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
Captured SpliceAI source record
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/1553923915
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000267.3%3Ac.8089_8093del…
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-29686025-TTTTC-GTTTT?datas…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-31359007-TTTTC-GTTTT?da…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000267.3%3Ac.8089…
- OncoKB ↗www.oncokb.org/gene/NF1/F2697_S2698delinsVL
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NF1+c.8089_8093delinsGTTTT
- 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.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NF1, a negative regulator of RAS, is inactivated by mutation or deletion in various solid and hematologic malignancies.
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.