About NF1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NF1 c.702_704delinsATT, p.(Tyr235Phe)
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, supporting rarity in population reference datasets and meeting PM2 at supporting strength.
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.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. 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. 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
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 NF1 VCEP v1.0.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 5 not met · 14 not assessed · 8 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.702_704delinsATT (p.Tyr235Phe) 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.
SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, but no REVEL or BayesDel score was available to support or refute a deleterious missense effect.
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets and meeting PM2 at supporting strength. Details ▾Hide ▴
Rule
PM2_Supporting
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
Not met · 5 · evaluated, threshold not reached
PM1 This variant has not been shown to lie in a well-established functional domain or statistically significant hotspot without benign variation. Cancer Hotspots did not identify a significant hotspot at residue Y235, so PM1 is not supported by the reviewed evidence. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots review did not show a statistically significant hotspot at Y235.
Still missing
- No residue-specific functional-domain evidence was identified.
Sources
BA1 This variant is absent from gnomAD v2.1 and v4.1 and is therefore well below any benign stand-alone population threshold. BA1 is not met. Details ▾Hide ▴
BS1 This variant is absent from gnomAD v2.1 and v4.1 and is therefore below benign strong population frequency thresholds. BS1 is not met. Details ▾Hide ▴
BP1 Available evidence does not support BP1. This variant is a missense change, and missense variation is a recognized variant class in NF1 interpretation rather than a class that is uniformly non-contributory. Details ▾Hide ▴
Evidence considered
- NF1 is interpreted with missense-specific criteria in the reviewed specification context.
Sources
BP4 SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), but no REVEL or BayesDel score was available to support a benign missense interpretation. Available computational evidence is insufficient to meet BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01.
- REVEL not available.
- BayesDel not available.
Still missing
- No REVEL score was available.
- No BayesDel score was available.
Sources
Not assessed · 14 · no assessment recorded
PS1 No pathogenic or likely pathogenic variant causing the same amino-acid change, p.(Tyr235Phe), was identified in the reviewed evidence, so PS1 was not established. Details ▾Hide ▴
PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 could not be applied. Details ▾Hide ▴
Evidence considered
- ClinVar query showed no exact record.
Still missing
- No trio-based or parentage-confirmed de novo report was identified.
Sources
PS3 No well-established functional study demonstrating a damaging effect of this exact variant was identified, so PS3 was not applied. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
- No validated variant-specific functional assay was identified.
Sources
PS4 No enrichment data, odds ratio, or multiple independent affected observations sufficient for PS4 were identified for this variant. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar.
- Variant absent from gnomAD v2.1 and v4.1.
Still missing
- No case-control data or multiple independent detailed clinical reports were identified.
Sources
PM6 No assumed de novo occurrence without full parentage confirmation was identified for this variant, so PM6 could not be applied. Details ▾Hide ▴
Evidence considered
- ClinVar query showed no exact record.
Still missing
- No de novo case report or submitter note was identified.
Sources
PP1 No segregation data were identified for this variant, so PP1 could not be applied. Details ▾Hide ▴
Evidence considered
- ClinVar query showed no exact record.
Still missing
- No informative family segregation report was identified.
Sources
PP2 Available evidence did not establish a gene-specific basis to apply PP2 for this missense variant, so PP2 was not assessed. Details ▾Hide ▴
Evidence considered
- NF1 specification metadata were available
- but no criterion-level local rule text was available in the reviewed files.
Still missing
- No reviewed NF1-specific missense-mechanism rule supporting PP2 application was identified.
Sources
PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), but no REVEL or BayesDel score was available to assess the missense effect itself. Available computational evidence is therefore insufficient to support PP3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01.
- REVEL not available.
- BayesDel not available.
Still missing
- No REVEL score was available.
- No BayesDel score was available.
Sources
PP4 No phenotype information was provided that was sufficiently specific to NF1 to support PP4 for this variant. Details ▾Hide ▴
Evidence considered
- Disease context is NF1
- but no patient-specific phenotype data were provided.
Still missing
- No case phenotype or clinical diagnostic details were available for review.
Sources
BS2 No observation of this variant in healthy adults with adequate penetrance context was identified, so BS2 could not be applied. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD.
Still missing
- No healthy-carrier evidence was identified.
Sources
BS3 No well-established functional study showing normal NF1 function for this exact variant was identified, so BS3 was not applied. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence.
Still missing
- No validated benign functional assay was identified.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 could not be applied. Details ▾Hide ▴
Evidence considered
- ClinVar query showed no exact record.
Still missing
- No informative pedigree showing lack of segregation was identified.
Sources
BP2 No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with another pathogenic variant, so BP2 could not be applied. Details ▾Hide ▴
Evidence considered
- ClinVar query showed no exact record.
Still missing
- No phase information was available.
Sources
BP5 No alternative molecular diagnosis or alternate cause for disease was identified from the reviewed evidence, so BP5 could not be applied. Details ▾Hide ▴
Evidence considered
- No patient-specific alternate diagnosis data were provided.
Still missing
- No patient-level differential diagnostic information was available.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant results in p.(Tyr235Phe), an amino-acid substitution, and does not fall into the default PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1 or 2 splice-site variants. SpliceAI also predicts no significant splice impact (max delta score 0.01), so available evidence does not support applying PVS1. Details ▾Hide ▴
Rule
PVS1 not applicable for this missense delins event under the reviewed PVS1 frameworks.
Evidence considered
- NF1 loss of function is an established disease mechanism
- but this specific variant is not a predicted loss-of-function event.
- SpliceAI max delta score 0.01.
Still missing
- No variant-specific RNA study was identified.
Sources
PM3 N/APM3 is intended for recessive disorders with evidence of the variant in trans with a pathogenic variant. NF1 is evaluated here in an autosomal dominant disease context, so PM3 is not applicable. Details ▾Hide ▴
Evidence considered
- NF1 disease context in the reviewed specification is autosomal dominant.
Sources
PM4 N/AAlthough described as a delins at the coding level, this variant results in a single amino-acid substitution, p.(Tyr235Phe), without a protein length change, so PM4 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Tyr235Phe).
Sources
pvs1_variant_assessment
PM5 N/AAvailable evidence did not identify any accepted same-residue pathogenic comparator, and the reviewed materials could not confirm that classic same-residue PM5 logic should be applied for this case. PM5 was therefore not used. Details ▾Hide ▴
Evidence considered
- PM5 candidate review found no usable comparator variants and marked classic PM5 eligibility as unsafe to assume.
Still missing
- No same-residue pathogenic comparator was identified.
- Classic PM5 semantics were not confirmed from the reviewed NF1 materials.
Sources
pm5_candidatescspec ↗
PP5 N/APP5 was not used. No ClinVar assertion was identified for this variant, and assertion-only criteria are not used as stand-alone evidence here. Details ▾Hide ▴
BP3 N/ABP3 applies to certain in-frame insertions or deletions in repetitive regions without known function. This variant produces a single amino-acid substitution rather than an in-frame length change, so BP3 is not applicable. Details ▾Hide ▴
Evidence considered
- Protein consequence is p.(Tyr235Phe).
Sources
pvs1_variant_assessment
BP6 N/ABP6 was not used. No ClinVar benign or likely benign assertion was identified for this variant, and assertion-only criteria are not used as stand-alone evidence here. Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous or certain noncoding variants without predicted splice impact. This variant is a missense change, so BP7 is not applicable. Details ▾Hide ▴
Identifiers
- Gene
- NF1
- Transcript
- NM_000267.3
- Coding (HGVS c.)
- NM_000267.3:c.702_704delinsATT
- Protein (HGVS p.)
- NP_000258.1:p.(Tyr235Phe)
- GRCh38
- chr17:31181757 GTA>ATT
- GRCh37
- chr17:29508775 GTA>ATT
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.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), but no REVEL or BayesDel score was available to support a benign missense interpretation. Available computational evidence is insufficient to meet BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01.
- REVEL not available.
- BayesDel not available.
Still missing
- No REVEL score was available.
- No BayesDel score was available.
Sources
PP3 SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), but no REVEL or BayesDel score was available to assess the missense effect itself. Available computational evidence is therefore insufficient to support PP3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01.
- REVEL not available.
- BayesDel not available.
Still missing
- No REVEL score was available.
- No BayesDel score was available.
Sources
BP7 N/ABP7 applies to synonymous or certain noncoding variants without predicted splice impact. This variant is a missense change, so BP7 is not applicable. 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
Recorded maximum delta 0.010
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.702_704delinsATT
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-29508775-GTA-ATT?dataset=g…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-31181757-GTA-ATT?datase…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000267.3%3Ac.702_…
- OncoKB ↗www.oncokb.org/gene/NF1/Y235F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NF1+c.702_704delinsATT
- 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.