About NF1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NF1 c.2033C>T, p.(Pro678Leu)
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: 0
Benign evidence criteria: 1
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple computational predictors support a benign effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.141, and BayesDel is -0.334865, which together argue against a damaging effect.
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: BP4 supporting; combination = 1 supporting benign, 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
229 / 1,613,768 alleles
gnomAD v4.1: 229 / 1,613,768 alleles. Recorded AF 0.000141904. Recorded homozygote count 1.
gnomAD v2.1
Absent from gnomAD v2.1.
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
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 · 8 not met · 11 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.2033C>T (p.Pro678Leu) variant has been reported in ClinVar, where most submissions classify it as likely benign or benign, with one submission classifying it as uncertain significance.
This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 229/1613768 alleles overall (AF 0.01419%), with the highest observed frequency in the African/African American population at 139/75006 alleles (AF 0.18532%) and one homozygote reported.
Available computational evidence supports no meaningful functional impact, with SpliceAI showing no predicted splice effect (maximum delta score 0.00), REVEL at 0.141, and BayesDel at -0.334865.
No criteria match.
Met · 1
BP4 SupportingMultiple computational predictors support a benign effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.141, and BayesDel is -0.334865, which together argue against a damaging effect. Details ▾Hide ▴
Rule
BP4 applies when multiple computational lines of evidence suggest no impact on gene or gene product.
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL score 0.141.
- BayesDel score -0.334865.
Sources
Not met · 8 · evaluated, threshold not reached
PS1 No evidence was identified showing that a different nucleotide change produces the same amino acid substitution with an established pathogenic classification. Details ▾Hide ▴
Rule
PS1 requires the same amino acid change as a known pathogenic variant.
Evidence considered
- No same-amino-acid pathogenic comparator was retrieved.
Still missing
- No same-amino-acid pathogenic comparator was identified.
Sources
PS4 This variant has been reported in ClinVar, but the available evidence does not show enrichment in affected individuals over controls, and the variant is also present in gnomAD. Details ▾Hide ▴
Rule
PS4 requires a significantly increased prevalence in affected individuals compared with controls.
Evidence considered
- ClinVar contains multiple submissions for this variant.
- The variant is present in gnomAD v4.1.
Still missing
- No case-control or statistically increased prevalence data were identified.
Sources
PM1 Available evidence does not show that codon 678 lies in a mutational hotspot or in a well-established critical region without benign variation, and Cancer Hotspots did not identify a statistically significant hotspot at this residue. Details ▾Hide ▴
Rule
PM1 requires location in a mutational hotspot or critical functional domain without benign variation.
Evidence considered
- Cancer Hotspots did not identify a statistically significant hotspot for NF1 p.(P678L).
Still missing
- No NF1 codon- or region-specific hotspot evidence was identified for residue 678.
Sources
PM2 This variant is present in gnomAD v4.1, with a highest observed population frequency of 0.18532% in the African/African American population, which is above the <0.1% rarity threshold used for PM2. Details ▾Hide ▴
Rule
PM2 requires absence or rarity below the applicable population threshold.
Evidence considered
- Absent from gnomAD v2.1.
- Present in gnomAD v4.1 at 229/1613768 alleles overall
- with African/African American AF 0.00185319.
Sources
PM5 No evidence was identified that a different missense change at codon 678 has been established as pathogenic. Details ▾Hide ▴
Rule
PM5 requires a novel missense change at an amino acid residue where a different pathogenic missense change has been seen before.
Evidence considered
- No pathogenic alternate amino acid substitution at residue 678 was identified from the retrieved evidence.
Still missing
- No pathogenic alternate missense substitution at the same codon was retrieved.
Sources
PP3 Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.141, and BayesDel is -0.334865. Details ▾Hide ▴
Rule
PP3 requires multiple computational lines of evidence supporting a deleterious effect.
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL score 0.141.
- BayesDel score -0.334865.
Sources
BA1 This variant does not meet the stand-alone benign frequency threshold because the highest observed population frequency in gnomAD v4.1 is 0.18532%, which is below the >1% BA1 threshold. Details ▾Hide ▴
Rule
BA1 requires frequency above the applicable stand-alone benign threshold.
Evidence considered
- Highest observed population AF in gnomAD v4.1 is 0.00185319.
Sources
BS1 This variant does not meet the strong benign frequency threshold because the highest observed population frequency in gnomAD v4.1 is 0.18532%, which is below the >0.3% BS1 threshold. Details ▾Hide ▴
Rule
BS1 requires allele frequency greater than the applicable strong benign threshold.
Evidence considered
- Highest observed population AF in gnomAD v4.1 is 0.00185319.
Sources
Not assessed · 11 · no assessment recorded
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant. Details ▾Hide ▴
Rule
PS2 requires a confirmed de novo occurrence in a patient with the disease and no family history, with maternity and paternity confirmed.
Evidence considered
- Retrieved records did not document a confirmed de novo event for NM_000267.3:c.2033C>T.
Still missing
- No documented parental testing with confirmed maternity and paternity.
Sources
PS3 No well-established functional study demonstrating a damaging effect of this exact variant was identified. Details ▾Hide ▴
Rule
PS3 requires well-established functional studies supportive of a damaging effect.
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence for p.(Pro678Leu).
Still missing
- No variant-specific functional assay showing abnormal NF1 function was retrieved.
Sources
PM6 No probable de novo occurrence without full parental confirmation was identified for this variant. Details ▾Hide ▴
Rule
PM6 requires an assumed de novo occurrence without confirmed maternity and paternity.
Evidence considered
- Retrieved records did not document an assumed de novo event for NM_000267.3:c.2033C>T.
Still missing
- No reported de novo occurrence lacking full parentage confirmation was found.
Sources
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Rule
PP1 requires cosegregation with disease in multiple affected family members.
Evidence considered
- No segregation information for NM_000267.3:c.2033C>T was identified in the retrieved records.
Still missing
- No informative family segregation data were retrieved.
Sources
PP2 Available evidence does not establish a gene-specific missense-only mechanism or a sufficiently low rate of benign missense variation to support PP2 for this variant. Details ▾Hide ▴
Rule
PP2 requires a gene in which missense variation is a common mechanism of disease and benign missense variation is uncommon.
Evidence considered
- No explicit NF1 PP2 rule was available in the retrieved framework materials.
Still missing
- No gene-specific PP2 framework was available for NF1 in the retrieved materials.
Sources
PP4 No individual-level phenotype data were identified that would support a highly specific clinical presentation for this variant. Details ▾Hide ▴
Rule
PP4 requires a patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.
Evidence considered
- ClinVar summary did not provide case-level phenotype specificity sufficient for PP4.
Still missing
- No case-level phenotype details were retrieved for variant carriers.
Sources
BS2 This variant is present in gnomAD v4.1 with one homozygote, but no phenotype information is available for population database participants, so this observation alone does not establish BS2. Details ▾Hide ▴
Rule
BS2 requires observation in healthy adult individuals for a disorder expected to be fully penetrant at an early age.
Evidence considered
- gnomAD v4.1 reports one homozygote.
Still missing
- No confirmed unaffected adult carriers with phenotype review were identified.
Sources
BS3 No well-established functional study demonstrating normal function of this exact variant was identified. Details ▾Hide ▴
Rule
BS3 requires well-established functional studies showing no damaging effect on protein function or splicing.
Evidence considered
- No variant-specific reviewed functional evidence was identified.
Still missing
- No variant-specific functional assay showing retained normal NF1 function was retrieved.
Sources
BS4 No nonsegregation data were identified for this variant. Details ▾Hide ▴
Rule
BS4 requires lack of segregation with disease in affected family members.
Evidence considered
- No nonsegregation evidence for NM_000267.3:c.2033C>T was identified.
Still missing
- No informative family data showing lack of segregation were retrieved.
Sources
BP2 No phase information with another pathogenic variant was identified. Details ▾Hide ▴
Rule
BP2 requires observation in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant in any inheritance pattern.
Evidence considered
- No phase data were identified for this variant.
Still missing
- No cis/trans data with another pathogenic variant were retrieved.
Sources
BP5 No alternate molecular explanation for the observed phenotype was identified from the available evidence. Details ▾Hide ▴
Rule
BP5 applies when a variant is found in a case with an alternate molecular basis for disease.
Still missing
- No case-level alternate diagnosis data were retrieved.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the available PVS1 assessments indicate that it does not fall within the default null-variant categories for PVS1 application. Details ▾Hide ▴
Rule
PVS1 applies to predicted loss-of-function variants when the variant type and gene mechanism support a null effect.
Evidence considered
- NF1 loss of function is an established disease mechanism.
- NM_000267.3:c.2033C>T is not a nonsense
- frameshift
- or canonical +/-1
- 2 splice variant.
Sources
PM3 N/ANo recessive-phase evidence was identified, and PM3 is not applicable to this case based on the available evidence. Details ▾Hide ▴
Rule
PM3 applies to recessive disorders with variants detected in trans.
PM4 N/AThis is a missense substitution and does not produce a protein length change from an in-frame insertion/deletion or stop-loss event. Details ▾Hide ▴
Rule
PM4 applies to protein length changes from in-frame insertions/deletions or stop-loss variants.
Evidence considered
- NM_000267.3:c.2033C>T results in p.(Pro678Leu).
PP5 N/AExternal classification assertions were identified in ClinVar, but reputable-source assertions alone were not used as stand-alone evidence for this criterion. Details ▾Hide ▴
Rule
PP5 is not used here as a stand-alone criterion based only on external assertions.
Evidence considered
- ClinVar contains Likely benign
- Benign
- and Uncertain significance submissions.
Sources
BP1 N/ABP1 is not applicable because missense variation is a recognized disease mechanism in NF1 and this is not a gene where primarily truncating variants alone account for disease. Details ▾Hide ▴
Rule
BP1 applies when missense variation occurs in a gene for which primarily truncating variants are known to cause disease.
Evidence considered
- No gene-specific framework supported BP1 use for NF1 missense variants.
Sources
BP3 N/AThis is not an in-frame deletion or insertion in a repetitive region without known function. Details ▾Hide ▴
Rule
BP3 applies to in-frame deletions/insertions in repetitive regions without known function.
BP6 N/ABenign and likely benign assertions are present in ClinVar, but external assertions alone were not used as stand-alone benign evidence for this criterion. Details ▾Hide ▴
Rule
BP6 is not used here as a stand-alone criterion based only on external assertions.
Evidence considered
- ClinVar contains 7 likely benign
- 4 benign
- and 1 uncertain significance submissions.
Sources
BP7 N/AThis is a missense variant and not a synonymous or deep intronic change for which BP7 would be considered. Details ▾Hide ▴
Rule
BP7 applies to synonymous or certain intronic variants with no predicted splicing impact and low conservation expectations.
Identifiers
- Gene
- NF1
- Transcript
- NM_000267.3
- Coding (HGVS c.)
- NM_000267.3:c.2033C>T
- Protein (HGVS p.)
- NP_000258.1:p.(Pro678Leu)
- GRCh38
- chr17:31226466 C>T
- GRCh37
- chr17:29553484 C>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
229 / 1,613,768 alleles
AF 0.000142 · 1 homozygotes · FAF 0.0016
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00014 · 229 / 1,613,768 alleles · 1 hom · FAF 0.0016
| African/African American139 / 75,006 | 0.0019 |
| East Asian32 / 44,880 | 0.00071 |
| Remaining individuals16 / 62,480 | 0.00026 |
| South Asian21 / 91,064 | 0.000231 hom |
| Admixed American9 / 59,964 | 0.00015 |
| European (non-Finnish)12 / 1,179,796 | 1e-05 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000141904; MAF= 0.01419%, 229/1613768 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00185319; MAF= 0.18532%, 139/75006 alleles, homozygotes = 0); grpmax FAF= 0.00160212.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingMultiple computational predictors support a benign effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.141, and BayesDel is -0.334865, which together argue against a damaging effect. Details ▾Hide ▴
Rule
BP4 applies when multiple computational lines of evidence suggest no impact on gene or gene product.
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL score 0.141.
- BayesDel score -0.334865.
Sources
PP3 Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.141, and BayesDel is -0.334865. Details ▾Hide ▴
Rule
PP3 requires multiple computational lines of evidence supporting a deleterious effect.
Evidence considered
- SpliceAI max delta score 0.00.
- REVEL score 0.141.
- BayesDel score -0.334865.
Sources
BP7 N/AThis is a missense variant and not a synonymous or deep intronic change for which BP7 would be considered. Details ▾Hide ▴
Rule
BP7 applies to synonymous or certain intronic variants with no predicted splicing impact and low conservation expectations.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.141. BayesDel score = -0.334865.
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
229 / 1,613,768 recorded alleles
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/variation/41669/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-29553484-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-31226466-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000267.3%3Ac.2033…
- OncoKB ↗www.oncokb.org/gene/NF1/P678L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=114429180
- 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
This variant is present in gnomAD v4.1 (AF= 0.000141904; MAF= 0.01419%, 229/1613768 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00185319; MAF= 0.18532%, 139/75006 alleles, homozygotes = 0); grpmax FAF= 0.00160212.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.141. BayesDel score = -0.334865.
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; COSV62204740, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.