About NF1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NF1 c.3479G>A, p.(Gly1160Asp)
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. 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, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare variant. Under generic ACMG/AMP 2015, absence from large population cohorts supports PM2 at supporting strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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: 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
0.060 maximum delta
Recorded SpliceAI maximum delta score: 0.060. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
5 reported laboratory submissions
2 Likely pathogenic · 2 Uncertain significance · 1 Pathogenic. ClinVar API review status: criteria provided, conflicting classifications.
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
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV104662397, n = 1 times).
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: 1 met · 23 not met · 0 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
NM_001042492.2:c.3479G>A (p.Gly1160Asp) in NF1 is a missense variant absent from gnomAD population databases (v2.1, v4.1, Canada v1.0), satisfying PM2 at supporting strength.
This variant does not meet PVS1 criteria, as it is a missense variant and does not fall into the null-variant buckets (nonsense, frameshift, canonical splice) defined by the ClinGen SVI PVS1 recommendations (PMC6185798).
No variant-specific functional studies (PS3/BS3), segregation data (PP1/BS4), de novo observations (PS2/PM6), case-control prevalence (PS4), or same-residue pathogenic comparators (PM5/PS1) were identified in ClinVar or the literature.
In silico predictions are conflicting: REVEL (0.851) supports a deleterious effect while BayesDel (0.15882) is in the benign range, and SpliceAI predicts no splice impact (max delta 0.06). These conflicting results preclude application of both PP3 and BP4.
ClinVar classification is Likely pathogenic with review status 'criteria provided, single submitter' (2★); conflicting submissions exist (2 LP, 2 VUS, 1 P). PP5 does not apply at this review level and BP6 is not met as no benign classification exists.
The NF1 CSPEC framework (ClinGen Neurofibromatosis and Schwannomatosis Expert Panel, Version 1.0) was retrieved but is incomplete (framework_complete=false, empty criteria). Generic ACMG/AMP 2015 combination rules (PMID:25741868) are applied for final classification.
With only one supporting pathogenic criterion (PM2) met and no benign criteria, this variant does not reach the threshold for Likely Pathogenic or Likely Benign classification under generic ACMG/AMP 2015 rules. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare variant. Under generic ACMG/AMP 2015, absence from large population cohorts supports PM2 at supporting strength. 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 · 23 · evaluated, threshold not reached
PS1 No evidence of a different nucleotide change at the same codon resulting in the same amino acid substitution that has been established as pathogenic. Neither the ClinVar records nor the literature identify a same-amino-acid PS1 comparator for p.Gly1160Asp. Details ▾Hide ▴
Evidence considered
- PM5 candidate search found no same-residue comparator variants
- no PS1 evidence identified in ClinVar or literature.
Still missing
- No systematic search for alternate nucleotide changes producing p.G1160D was performed beyond ClinVar.
Sources
clinvar ↗pm5_candidates
PS2 No de novo observation confirmed for NM_001042492.2:c.3479G>A. No paper in the case folder reports a de novo finding with confirmed maternity and paternity for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data available in ClinVar submissions
- literature
- or any other source.
Still missing
- No parental testing data available.
PS3 No variant-specific functional data identified for p.Gly1160Asp. OncoKB classifies this variant as 'Unknown Oncogenic Effect'. No published functional studies in the literature packet directly test this variant or a systematically characterized range that includes position 1160. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional studies identified in literature packet
- no systematic range characterization covering residue 1160.
Still missing
- No functional assay data exists for this variant in the literature.
Sources
PS4 No case-control prevalence data available. While this variant has been reported to ClinVar in multiple clinical testing submissions, no peer-reviewed publication provides variant-specific prevalence data in affected versus control populations. The ClinVar criterion-lead papers are guidelines or consensus statements that do not provide variant-specific case observations. Details ▾Hide ▴
Evidence considered
- ClinVar: 5 clinical submissions (2 LP
- 2 VUS
- 1 P)
- no case-control data
- guideline/consensus papers cited do not contain variant-specific case observations.
Still missing
- No peer-reviewed prevalence or case-control data for this variant.
Sources
PM1 This variant (p.Gly1160Asp) is not located in a statistically significant mutational hotspot per cancerhotspots.org. Position 1160 falls within the tubulin-binding domain (TBD/pre-GRD region) of neurofibromin, but no literature in the case folder specifically establishes this residue or domain as a critical functional domain satisfying PM1 under the NF1 CSPEC framework or generic ACMG/AMP criteria. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: not significant
- position 1160 in TBD/pre-GRD domain but no domain-level PM1 evidence in case folder.
Still missing
- Domain-level functional characterization of the TBD region (aa ~1095-1236) for NF1 PM1 application not retrieved.
Sources
pvs1_gene_context
PM5 No confirmed pathogenic variant at the same amino acid position (Gly1160) with a different amino acid change was identified. The automated PM5 candidate harvest failed to find same-residue comparator variants in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates
- 0 expert-panel P/LP candidates
- candidate_summary empty.
Still missing
- No systematic manual search for same-residue pathogenic comparators beyond automated ClinVar harvesting.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation with unconfirmed maternity/paternity reported for this variant. PM6 requires at least one de novo finding where both parents are not confirmed. Details ▾Hide ▴
Evidence considered
- No de novo data in any source.
Still missing
- No de novo testing data available.
PP1 No segregation data available for this variant. PP1 requires co-segregation of the variant with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation data in ClinVar or literature.
Still missing
- No family studies or segregation analysis available.
PP2 Insufficient data to determine if NF1 has a low rate of benign missense variation. The HCI prior was not available for this variant, and no gene-level missense constraint score was retrieved to satisfy generic ACMG/AMP PP2 requirements. Details ▾Hide ▴
Evidence considered
- HCI prior: not found
- no gene-level missense Z-score or constraint metric available for NF1 to assess PP2 eligibility.
Still missing
- No gene-level missense constraint metric (Z-score
- LOEUF
- pLI) retrieved for NF1.
PP3 In silico predictions are conflicting. REVEL score of 0.851 predicts a deleterious effect, but BayesDel score of 0.159 is in the benign range. SpliceAI predicts no splice impact (max delta 0.06). Under generic ACMG/AMP, PP3 requires multiple lines of computational evidence uniformly supporting a deleterious effect, which is not satisfied by these conflicting results. Details ▾Hide ▴
Evidence considered
- REVEL: 0.851 (pathogenic-range)
- BayesDel: 0.15882 (benign-range)
- SpliceAI max delta: 0.06 (no splice effect).
Still missing
- No conservation or evolutionary data available to resolve conflicting in silico predictions.
Sources
PP4 No patient phenotype or family history data available to assess whether the clinical presentation is highly specific for NF1 (neurofibromatosis type 1). PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data in any source.
Still missing
- No patient phenotype information available.
PP5 ClinVar review status for this variant is 'criteria provided, single submitter' (2★). Per adjudication rules, PP5 applies at supporting strength only when a 3★ expert panel classification is present. The CSPEC framework does not override this threshold. Details ▾Hide ▴
Evidence considered
- ClinVar 2★ review status
- conflicting submissions (2 LP
- 2 VUS
- 1 P)
- no expert panel classification.
Sources
BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires allele frequency >5% in population databases. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD datasets
- AF = 0.
Sources
BS1 BS1 requires allele frequency greater than expected for the disorder (>0.3% non-VCEP). This variant is absent from all population databases, so BS1 is not met. Details ▾Hide ▴
BS2 No evidence that this variant has been observed in a healthy adult individual in trans with a known pathogenic dominant variant. BS2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No co-occurrence or phasing data available.
Still missing
- No data on variant co-occurrence with known pathogenic NF1 variants.
BS3 No well-established functional studies demonstrate no deleterious effect of this variant. OncoKB classifies this variant as 'Unknown Oncogenic Effect', and no published functional assays were identified in the literature packet. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional studies in literature demonstrating benign effect.
Still missing
- No functional data available to support or refute a benign effect.
Sources
BS4 No family segregation data available. BS4 requires lack of segregation of the variant with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family studies available.
BP1 NF1 is not a gene where only truncating variants cause disease; missense variants are a well-established pathogenic mechanism in NF1. BP1 requires the variant class (missense) in a gene where primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- NF1 LOF mechanism supported
- but missense variants are also a common cause of NF1
- BP1 requires truncating-only disease mechanism.
Sources
pvs1_gene_context
BP2 No evidence that this variant is observed in trans with a known pathogenic variant for a fully penetrant dominant disorder. No co-occurrence or phasing data available. Details ▾Hide ▴
Evidence considered
- No co-occurrence data available.
Still missing
- No phasing or co-occurrence data.
BP4 Multiple lines of computational evidence do NOT uniformly suggest no impact. REVEL score of 0.851 supports a deleterious effect, contradicting any benign computational assessment. BP4 requires multiple lines of evidence suggesting no impact on gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.851 (deleterious
- contradictory to BP4)
- BayesDel: 0.15882 (benign-range)
- SpliceAI: no splice impact. Not a uniform benign prediction.
Sources
BP5 No evidence that this variant is found in a case with an established alternative molecular basis for disease. BP5 requires observation in a case with a known pathogenic variant in an alternative gene that explains the phenotype. Details ▾Hide ▴
Evidence considered
- No alternative molecular diagnosis information available.
Still missing
- No data on alternative molecular diagnoses.
BP6 ClinVar does not classify this variant as benign or likely benign. The ClinVar classification is Likely pathogenic with conflicting submissions (2 LP, 2 VUS, 1 P). BP6 would require a reputable source classifying as benign at 3★ review level. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Likely pathogenic
- review status 2★
- no benign classification from any source.
Sources
PS5 No expert panel classification of this variant as pathogenic in ClinVar. The ClinVar review status is 'criteria provided, single submitter' (2★). A 3★ expert panel classification is required for PS5 application. Details ▾Hide ▴
Evidence considered
- ClinVar review status: criteria provided
- single submitter (2★)
- no expert panel review
- conflicting submissions (2 LP
- 2 VUS
- 1 P).
Still missing
- No ClinGen expert panel review for this variant.
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Gly1160Asp), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). Does not fall into the default generic PVS1 null-variant buckets per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket: other
- apply_generic_pvs1_framework: false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders (variant detected in trans with a pathogenic variant). NF1 is an autosomal dominant disorder. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes due 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 with unknown function. This is a substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a missense variant (p.Gly1160Asp), not synonymous. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- NF1
- Transcript
- NM_001042492.2
- Coding (HGVS c.)
- NM_001042492.2:c.3479G>A
- Protein (HGVS p.)
- NP_001035957.1:p.(Gly1160Asp)
- GRCh38
- chr17:31232864 G>A
- GRCh37
- chr17:29559882 G>A
- ClinVar
- 861799
- COSMIC
- COSV104662397
Gene diagram
Every interpreted variant in NF1, mapped onto the exon structure of NM_001042492.2. Select a row to find it on the plot.
NF1NM_001042492.2
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
- 0.851
- BayesDel
- 0.159
How the predictions were used
PP3 In silico predictions are conflicting. REVEL score of 0.851 predicts a deleterious effect, but BayesDel score of 0.159 is in the benign range. SpliceAI predicts no splice impact (max delta 0.06). Under generic ACMG/AMP, PP3 requires multiple lines of computational evidence uniformly supporting a deleterious effect, which is not satisfied by these conflicting results. Details ▾Hide ▴
Evidence considered
- REVEL: 0.851 (pathogenic-range)
- BayesDel: 0.15882 (benign-range)
- SpliceAI max delta: 0.06 (no splice effect).
Still missing
- No conservation or evolutionary data available to resolve conflicting in silico predictions.
Sources
BP4 Multiple lines of computational evidence do NOT uniformly suggest no impact. REVEL score of 0.851 supports a deleterious effect, contradicting any benign computational assessment. BP4 requires multiple lines of evidence suggesting no impact on gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.851 (deleterious
- contradictory to BP4)
- BayesDel: 0.15882 (benign-range)
- SpliceAI: no splice impact. Not a uniform benign prediction.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a missense variant (p.Gly1160Asp), not synonymous. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.851. BayesDel score = 0.15882.
8 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 25741868 ↗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.Seminal ACMG/AMP standards and guidelines for sequence variant interpretation. This is a methodological framework paper and does not discuss any specific NF1 variants.Does not name this variant
-
PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Describes a standardized DNA variant scoring system for Mendelian disorders. This is a methods paper and does not discuss any specific NF1 variants.Does not name this variant
-
PMID 37751797 ↗Reassessment of the NF1 variants of unknown significance found during the 20-year activity of a genetics diagnostic laboratory.Martorana D et al. · 2023Reassessment of NF1 variants of unknown significance from a 20-year diagnostic laboratory experience. The abstract discusses general VUS reclassification methodology. The specific variant NM_001042492.2:c.3479G>A was not confirmed in the abstract; full text is unavailable for verification.Does not name this variant
-
PMID 17636453 ↗Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors.Radtke HB et al. · 2007Guidelines for genetic counseling of NF1 patients and families from the National Society of Genetic Counselors. This is a clinical practice guideline and does not discuss any specific NF1 variants.Does not name this variant
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PMID 25394175 ↗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. · 2015ACMG/NSGC practice guideline for referral indications for cancer predisposition assessment. This is a clinical practice guideline and does not discuss any specific NF1 variants.Does not name this variant
-
PMID 26324357 ↗American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.Robson ME et al. · 2015ASCO policy statement update on genetic and genomic testing for cancer susceptibility. This is a policy statement and does not discuss any specific NF1 variants.Does not name this variant
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PMID 24893135 ↗Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.Lenders JW et al. · 2014Endocrine Society clinical practice guideline for pheochromocytoma and paraganglioma. This is a specialty guideline and does not discuss any specific NF1 variants.Does not name this variant
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PMID 33939658 ↗The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.NANETS consensus guidelines for surveillance and management of metastatic pheochromocytoma and paraganglioma. This is a specialty guideline and does not discuss any specific NF1 variants.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 0.060
Open source ↗
ClinVar
2 Likely pathogenic · 2 Uncertain significance · 1 Pathogenic
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/variation/861799/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-29559882-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-31232864-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-31232864-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001042492.2%3Ac.3…
- OncoKB ↗www.oncokb.org/gene/NF1/G1160D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=134121904
- 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 has been reported in ClinVar as Likely pathogenic (2 clinical laboratories) and as Uncertain significance (2 clinical laboratories) and as Pathogenic (1 clinical laboratory). (ClinVarID = 861799)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.851. BayesDel score = 0.15882.
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 previously been reported in somatic cancers (COSMIC; COSV104662397, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.