About NF1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NF1 c.3118A>T, p.(Lys1040Ter)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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. 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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong
NM_000267.3:c.3118A>T is a nonsense variant predicted to result in premature termination at codon 1040 (p.Lys1040Ter) in exon 24 of 60. NF1 loss-of-function is a well-established disease mechanism for neurofibromatosis type 1, an autosomal dominant disorder. Nonsense-mediated decay is expected given the premature stop codon is located well upstream of the final exon-exon junction. The truncated protein loses critical C-terminal functional domains including the GAP-related domain (GRD, aa 1198-1530). No downgrade considerations apply under the ClinGen SVI PVS1 decision framework (PMC6185798).
PM2Moderate
PM2 · moderate
This variant is absent from all queried population databases: gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Complete absence across large population cohorts is consistent with a rare pathogenic variant and meets the PM2 threshold of allele frequency below 0.1%.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
ClinGen Neurofibromatosis and Schwannomatosis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NF1 Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
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
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. 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 identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 18 not met · 0 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000267.3:c.3118A>T (p.Lys1040Ter) is a nonsense variant in exon 24 of the NF1 gene, predicted to result in premature termination and nonsense-mediated decay with loss of critical C-terminal functional domains including the GAP-related domain. NF1 loss-of-function is a well-established mechanism for neurofibromatosis type 1. Under the ClinGen SVI PVS1 decision framework (PMC6185798), this meets PVS1 at very_strong strength.
This variant is absent from all queried population databases, including gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a rare pathogenic variant and meeting PM2 at moderate strength.
The NF1 ClinGen VCEP specification (Version 1.0) was identified but contains no criteria-level rules. Adjudication was performed using the generic ACMG/AMP 2015 framework (Richards et al., PMID:25741868). Under generic ACMG/AMP combination rules, one Very_Strong (PVS1) plus one Moderate (PM2) supports a classification of Likely Pathogenic.
No criteria match.
Met · 2
PVS1 Very strongNM_000267.3:c.3118A>T is a nonsense variant predicted to result in premature termination at codon 1040 (p.Lys1040Ter) in exon 24 of 60. NF1 loss-of-function is a well-established disease mechanism for neurofibromatosis type 1, an autosomal dominant disorder. Nonsense-mediated decay is expected given the premature stop codon is located well upstream of the final exon-exon junction. The truncated protein loses critical C-terminal functional domains including the GAP-related domain (GRD, aa 1198-1530). No downgrade considerations apply under the ClinGen SVI PVS1 decision framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Nonsense variant (K1040*) in exon 24 of 60
- NF1 loss-of-function is a well-established germline disease mechanism for neurofibromatosis type 1
- NMD expected — premature stop codon at aa 1040 of 2818
- with 36 exons downstream
- Truncation removes GAP-related domain (GRD) and other critical C-terminal domains
- NM_000267.3 is the ClinGen VCEP-preferred transcript for NF1
Sources
PM2 ModerateThis variant is absent from all queried population databases: gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Complete absence across large population cohorts is consistent with a rare pathogenic variant and meets the PM2 threshold of allele frequency below 0.1%. 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 · 18 · evaluated, threshold not reached
PS2 No de novo observation data are available for this variant. No publications or ClinVar submissions report a confirmed de novo occurrence with both maternity and paternity confirmed. Details ▾Hide ▴
Still missing
- No de novo data available in ClinVar
- literature
- or case materials
PS3 No variant-specific functional studies were identified for NM_000267.3:c.3118A>T (p.Lys1040Ter). OncoKB curates this variant as Likely Oncogenic/Likely Loss-of-function, but this represents a knowledgebase annotation rather than primary experimental data. None of the five reviewed publications directly tested or reported functional data for this exact variant. No systematic range characterization encompassing codon 1040 was identified. Details ▾Hide ▴
Evidence considered
- OncoKB annotation: Likely Oncogenic
- Likely Loss-of-function — curated knowledge
- not primary experimental evidence
Still missing
- No variant-specific functional studies available
- No systematic saturation mutagenesis or tiling screen encompassing codon 1040
Sources
PS4 No case-control or cohort data are available for this variant. The variant is absent from ClinVar with zero submissions, and no publication reports the variant in affected individuals versus controls. Details ▾Hide ▴
Still missing
- No prevalence data in affected individuals
- Absent from ClinVar
PM1 The variant at codon 1040 is not located within a well-established critical functional domain. Neurofibromin's GAP-related domain (GRD) spans approximately residues 1198-1530, and codon 1040 lies upstream of this region. Cancerhotspots.org does not identify this residue as a statistically significant hotspot. The variant's truncating effect that removes downstream domains is already captured under PVS1; applying PM1 for domain removal by truncation would constitute double-counting. Details ▾Hide ▴
Evidence considered
- Variant at codon 1040 is upstream of the GRD (aa 1198-1530)
- Not in a statistically significant mutational hotspot per cancerhotspots.org
PM6 No de novo observation (without confirmation of maternity and paternity) is available for this variant. No publications or ClinVar submissions report a de novo occurrence. Details ▾Hide ▴
Still missing
- No de novo reports in literature or ClinVar
PP1 No co-segregation data are available. No publications report this variant segregating with disease in multiple affected family members. Details ▾Hide ▴
Still missing
- No segregation data available
PP3 In silico evidence is limited and insufficient for PP3. SpliceAI predicts no significant splice impact (max delta score 0.02). BayesDel score is 0.652534, which is weakly suggestive of deleteriousness but represents a single borderline predictor. REVEL and HCI prior scores are unavailable. For a nonsense variant with established PVS1 at very_strong, the deleterious effect of protein truncation is already fully captured, and PP3 would constitute double-counting the same molecular evidence. Details ▾Hide ▴
Evidence considered
- SpliceAI: no splice impact (max delta 0.02)
- BayesDel: 0.652534 (borderline
- single predictor)
Still missing
- REVEL score not available
- No HCI prior probability
Sources
spliceai ↗bayesdel
PP4 No patient phenotype or family history data are available in the case materials. Clinical information is required to assess whether the phenotype is highly specific for neurofibromatosis type 1. Details ▾Hide ▴
Still missing
- No phenotypic data available
PP5 This variant is absent from ClinVar with zero submissions and no classification from any submitter. No reputable source has reported this variant as pathogenic. The variant does not meet the PP5 threshold of a reputable source reporting pathogenicity without independent verification. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar — no submissions
- no classification
Sources
BA1 This variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). The allele frequency is 0%, well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% in all gnomAD populations
Sources
BS1 The variant is absent from all population databases. The allele frequency of 0% is below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% in all gnomAD populations
Sources
BS2 No data are available regarding observation of this variant in healthy adult controls. The variant is absent from population databases and no case reports describe it in unaffected individuals. Details ▾Hide ▴
Still missing
- No control population data beyond gnomAD absence
BS3 No functional studies of any kind were identified for this variant. There are no experimental data demonstrating a neutral or benign functional effect for NM_000267.3:c.3118A>T. Details ▾Hide ▴
Still missing
- No functional data available
BS4 No segregation data are available. No publications report lack of segregation of this variant with disease in affected families. Details ▾Hide ▴
Still missing
- No segregation data available
BP2 No data are available regarding the phase of this variant relative to other NF1 variants. No observation in trans with a known pathogenic variant or in cis with a pathogenic variant has been reported. Details ▾Hide ▴
Still missing
- No phasing data available
BP4 Multiple lines of computational evidence do not support a benign interpretation. SpliceAI predicts no splice impact (max delta 0.02), but BayesDel (0.652534) weakly suggests a deleterious effect. The in silico evidence is conflicting and does not meet the BP4 threshold of multiple predictors consistently suggesting no impact. Details ▾Hide ▴
Evidence considered
- SpliceAI: no splice impact (max delta 0.02)
- BayesDel: 0.652534 — weakly suggestive of deleterious effect
Sources
spliceai ↗bayesdel
BP5 No data are available regarding this variant being found in a case with an alternate molecular basis for disease. No published case reports describe this variant alongside another explanatory genetic finding. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available
BP6 This variant is absent from ClinVar with zero submissions. No reputable source has reported this variant as benign. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar — no submissions
- no classification
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to the same amino acid change as a previously established pathogenic variant. This is a nonsense (truncating) variant for which the null effect is already captured by PVS1 at very_strong strength. Applying PS1 would constitute double-counting the same molecular evidence. Details ▾Hide ▴
No further detail was recorded.
PM3 N/ASkipped per instruction: trivially not applicable. NF1 is an autosomal dominant disorder; PM3 (in trans with pathogenic variant for recessive disorders) is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per instruction: trivially not applicable. PM4 applies to in-frame deletions/insertions or stop-loss variants. This is a substitution (nonsense) variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 applies to novel missense changes at an amino acid residue where a different pathogenic missense change has been established. This variant is a nonsense change (p.Lys1040Ter), not a missense variant. The PM5 candidate search confirmed no classic same-residue comparator variants are available. PM5 semantics are not applicable to nonsense variants. Details ▾Hide ▴
Evidence considered
- Variant is a nonsense change (K1040*)
- not a missense variant
- PM5 candidate search confirmed no applicable same-residue comparators
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes where missense is a common disease mechanism and benign missense variation is rare. This is a nonsense (truncating) variant, not a missense change. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a nonsense (truncating) variant, which is the established disease mechanism for NF1. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ASkipped per instruction: trivially not applicable. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense change (c.3118A>T, p.Lys1040Ter), not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a criterion in the standard ACMG/AMP 2015 framework. The NF1 VCEP specifications (Version 1.0) contain no criteria rules and an empty rule_payload, providing no definition for PS5. No applicable framework defines this criterion. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- NF1
- Transcript
- NM_000267.3
- Coding (HGVS c.)
- NM_000267.3:c.3118A>T
- Protein (HGVS p.)
- NP_000258.1:p.(Lys1040Ter)
- GRCh38
- chr17:31230846 A>T
- GRCh37
- chr17:29557864 A>T
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
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
- Not available
- BayesDel
- 0.653
How the predictions were used
PP3 In silico evidence is limited and insufficient for PP3. SpliceAI predicts no significant splice impact (max delta score 0.02). BayesDel score is 0.652534, which is weakly suggestive of deleteriousness but represents a single borderline predictor. REVEL and HCI prior scores are unavailable. For a nonsense variant with established PVS1 at very_strong, the deleterious effect of protein truncation is already fully captured, and PP3 would constitute double-counting the same molecular evidence. Details ▾Hide ▴
Evidence considered
- SpliceAI: no splice impact (max delta 0.02)
- BayesDel: 0.652534 (borderline
- single predictor)
Still missing
- REVEL score not available
- No HCI prior probability
Sources
spliceai ↗bayesdel
BP4 Multiple lines of computational evidence do not support a benign interpretation. SpliceAI predicts no splice impact (max delta 0.02), but BayesDel (0.652534) weakly suggests a deleterious effect. The in silico evidence is conflicting and does not meet the BP4 threshold of multiple predictors consistently suggesting no impact. Details ▾Hide ▴
Evidence considered
- SpliceAI: no splice impact (max delta 0.02)
- BayesDel: 0.652534 — weakly suggestive of deleterious effect
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense change (c.3118A>T, p.Lys1040Ter), not a synonymous variant. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). BayesDel score = 0.652534.
5 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
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PMID 10543400 ↗Evaluation of the protein truncation test and mutation detection in the NF1 gene: mutational analysis of 15 known and 40 unknown mutations.Reports the protein truncation test methodology for NF1 mutation detection and characterizes 21 mutations in a panel of 40 NF1 patients, including R416X, R440X, R1276X, R1362X, and R2214X. NM_000267.3:c.3118A>T (p.Lys1040Ter) was not identified among the reported variants.Does not name this variant
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PMID 10862084 ↗Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.Reports exhaustive NF1 mutation analysis in 67 unrelated patients, identifying 64 germline mutations including 25 nonsense, 12 frameshift, 19 splice, 6 missense, and structural variants. NM_000267.3:c.3118A>T (p.Lys1040Ter) was not among the reported mutations.Does not name this variant
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PMID 12509763 ↗Targeting RAS signalling pathways in cancer therapy.Review article describing RAS signaling pathways and their role in cancer, with discussion of NF1 as a RAS GAP and tumor suppressor. Discusses therapeutic targeting of RAS pathways. NM_000267.3:c.3118A>T is not mentioned at any level.Does not name this variant
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PMID 14722914 ↗Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene.Screening study of 500 NF1 patients for deletions of the NF1 gene using microsatellite markers. Focused on large deletions, not point mutations. NM_000267.3:c.3118A>T is not mentioned in the abstract.Does not name this variant
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PMID 19573811 ↗Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis.Investigates NF1 inactivation in sporadic gliomas through proteasomal degradation and genetic loss. Reports NF1 mutations and deletions in glioblastoma but does not list or discuss NM_000267.3:c.3118A>T (p.Lys1040Ter) specifically.Does not name this variant
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 0.020
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.3118A%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-29557864-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-31230846-A-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-31230846-A-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000267.3%3Ac.3118…
- OncoKB ↗www.oncokb.org/gene/NF1/K1040*
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NF1+c.3118A%3ET
- 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 = 0.02). BayesDel score = 0.652534.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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.