0%
NF1c.3496G>CUncertain significance
Print report
Variant interpretation report

NF1 c.3496G>C, p.(Gly1166Arg)

NM_001042492.3:c.3496G>C NP_001035957.1:p.(Gly1166Arg) View identifiers
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.

About NF1

No gene-level summary was recorded for this case.

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
PM2Moderate
PM2 · moderate

NM_001042492.3:c.3496G>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes), indicating it is not a common population variant and meets PM2 at moderate strength (allele frequency <0.1% in all population databases queried).

PP3Supporting
PP3 · supporting

SpliceAI predicts a significant donor loss at the exon 26–intron 26 boundary (DS_DL = 0.76, well above the 0.2 threshold), consistent with the variant altering the last nucleotide of exon 26 (c.3496G>C at position −1 of the donor splice site). REVEL (0.51) is borderline; BayesDel (0.053) is below the pathogenic threshold. The SpliceAI donor loss prediction provides in silico support for a deleterious effect.

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 moderate, PP3 supporting; combination = 1 moderate + 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.

SpliceAI score
0.760 maximum delta

Recorded SpliceAI maximum delta score: 0.760. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
2 reported laboratory submissions

1 Pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

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
COSMIC ↗Cancer Hotspots ↗
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 · 13 not met · 6 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_001042492.3:c.3496G>C (p.Gly1166Arg) is a missense variant in NF1 affecting the last nucleotide of exon 26.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at moderate strength.

SpliceAI predicts a donor loss at the exon 26–intron 26 boundary with a delta score of 0.76, meeting PP3 at supporting strength.

This variant has been reported in ClinVar as Pathogenic by Ambry Genetics and Likely pathogenic by GeneDx, both with criteria provided, single submitter review status.

No variant-specific functional data (PS3), de novo reports (PS2/PM6), or co-segregation data (PP1/BS4) are available.

Two publications associated with this variant via ClinVar (PMID:24789688, PMID:25394175) were reviewed; neither mentions NM_001042492.3:c.3496G>C specifically.

The NF1 ClinGen Neurofibromatosis and Schwannomatosis Expert Panel specification (Version 1.0) contains no structured criteria rules; assessment follows generic ACMG/AMP 2015 framework.

Met · 2

PM2 ModerateNM_001042492.3:c.3496G>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes), indicating it is not a common population variant and meets PM2 at moderate strength (allele frequency <0.1% in all population databases queried). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1.
  • Absent from gnomAD v4.1.
  • Absent from gnomAD-Canada v1.0.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingSpliceAI predicts a significant donor loss at the exon 26–intron 26 boundary (DS_DL = 0.76, well above the 0.2 threshold), consistent with the variant altering the last nucleotide of exon 26 (c.3496G>C at position −1 of the donor splice site). REVEL (0.51) is borderline; BayesDel (0.053) is below the pathogenic threshold. The SpliceAI donor loss prediction provides in silico support for a deleterious effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI delta score (donor loss) = 0.76
  • predicting disruption of the exon 26 donor splice site.
  • REVEL = 0.51 (borderline pathogenic).
  • BayesDel = 0.053 (below pathogenic threshold).
Still missing
  • Confirmation by RNA studies would strengthen the splice prediction.
Sources
spliceai ↗revelbayesdel

Not met · 13 · evaluated, threshold not reached

PS2 No de novo occurrence data (maternity/paternity confirmed) was identified for this variant in any available source. Details ▾Hide ▴
Evidence considered
  • No de novo reports found.
Still missing
  • De novo occurrence data not available.
PS3 No experimental functional data exists for NM_001042492.3:c.3496G>C or a systematically characterized range that includes it. OncoKB reports no variant-specific reviewed functional evidence. SpliceAI predicts a donor loss (delta 0.76) but this is in silico prediction, not functional data. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional studies identified.
  • SpliceAI donor loss prediction is computational
  • not experimental.
Still missing
  • No variant-specific functional assays in the literature.
  • RNA studies to confirm aberrant splicing have not been performed.
Sources
oncokb ↗spliceai ↗
PS4 ClinVar submission SCV002617250 (Ambry Genetics) states the variant has been detected in multiple unrelated individuals with NF1 clinical suspicion, but no specific case counts, allele frequencies in cases vs controls, or statistical analysis are available. Without quantifiable data, PS4 cannot be met. Details ▾Hide ▴
Evidence considered
  • Ambry Genetics internal data mentions multiple unrelated individuals with NF1 suspicion
  • but no case counts provided.
Still missing
  • Specific case counts and statistical comparison to control populations are needed.
Sources
clinvar ↗
PM1 Position Gly1166 is not located within a statistically significant mutational hotspot (cancerhotspots.org reports no significant hotspot at this residue). No VCEP/CSPEC-defined critical functional domain encompasses this residue. The variant lies outside the GRD (GAP-related domain, residues ~1198–1530) and no published evidence identifies this position as a critical functional domain. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: no significant hotspot at position 1166.
  • Residue 1166 is outside the GRD (aa 1198–1530).
Still missing
  • Domain-level functional characterization of the region around residue 1166 is not available.
PM6 No de novo occurrence data (maternity/paternity confirmed) was identified for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports found.
Still missing
  • De novo data not available.
PP5 ClinVar classification is 'Pathogenic' and 'Likely pathogenic' with review status 'criteria provided, single submitter' (not 3-star expert panel). Under the applied framework, PP5 at supporting strength requires ClinVar 3-star expert panel review, which is not met. Neither cited ClinVar submission (Ambry Genetics, GeneDx) represents an expert panel classification. Details ▾Hide ▴
Evidence considered
  • ClinVar: Pathogenic (Ambry Genetics
  • single submitter) and Likely pathogenic (GeneDx
  • single submitter).
  • Review status: criteria provided
  • single submitter (not 3-star expert panel).
Still missing
  • No 3-star expert panel classification available.
Sources
clinvar ↗
BA1 The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada. BA1 requires an allele frequency >1%, which is not met. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0 in all gnomAD datasets
  • does not meet >1% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 The variant is absent from all population databases. BS1 requires an allele frequency >0.3%, which is not met. Details ▾Hide ▴
Evidence considered
  • Allele frequency = 0
  • does not meet >0.3% threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS3 No well-established in vitro or in vivo functional studies demonstrate no deleterious effect for this variant. Details ▾Hide ▴
Evidence considered
  • No benign functional data identified.
BP4 Multiple in silico tools predict a deleterious effect. SpliceAI predicts a donor loss with delta score 0.76. REVEL score (0.51) is borderline pathogenic. The evidence does not support a benign in silico consensus. Details ▾Hide ▴
Evidence considered
  • SpliceAI delta = 0.76 (donor loss
  • deleterious prediction).
  • REVEL = 0.51 (borderline
  • not clearly benign).
Sources
spliceai ↗revelbayesdel
BP5 No ClinVar submission classifies this variant as benign or likely benign. The variant is reported as Pathogenic and Likely pathogenic by two clinical laboratories. Details ▾Hide ▴
Evidence considered
  • All ClinVar submissions (2/2) classify as Pathogenic or Likely pathogenic.
Sources
clinvar ↗
BP6 ClinVar classification is Pathogenic/Likely pathogenic; BP6 requires a reputable source to classify the variant as benign. Additionally, no 3-star expert panel benign classification exists. Details ▾Hide ▴
Evidence considered
  • No benign ClinVar submissions for this variant.
Sources
clinvar ↗
PS5 No established pathogenic variant at the same position with a different amino acid change was identified. The ClinVar classification for this variant is 'criteria provided, single submitter' (not 3-star expert panel), which does not independently satisfy PS5 under the applied framework. Details ▾Hide ▴
Evidence considered
  • ClinVar single submitter classification
  • no same-residue comparators found.
Sources
clinvar ↗

Not assessed · 6 · no assessment recorded

PP1 No co-segregation data is available for this variant. Details ▾Hide ▴
Still missing
  • No family co-segregation data.
PP2 No HCI prior score or gene-level missense constraint metric is available for NF1 to determine whether the gene has a low rate of benign missense variation. The NF1 VCEP specification does not provide PP2 guidance. Details ▾Hide ▴
Evidence considered
  • HCI prior: not found for this variant.
Still missing
  • Gene-level missense constraint data (e.g.
  • Z-score
  • missense depletion) not available.
PP4 No patient phenotype or clinical data is available for this case. PP4 requires that the patient's phenotype is highly specific to the gene/disease. Details ▾Hide ▴
Still missing
  • Patient phenotype information not provided.
BS2 No data on observation in healthy adults (e.g., homozygous or in trans with a pathogenic variant) is available. Details ▾Hide ▴
Still missing
  • No data on observation in healthy adult controls.
BS4 No co-segregation data is available to evaluate lack of segregation with disease. Details ▾Hide ▴
Still missing
  • No family co-segregation data.
BP2 No data on observation in trans with a pathogenic variant in a recessive disorder (NA — NF1 is autosomal dominant). Details ▾Hide ▴

No further detail was recorded.

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001042492.3:c.3496G>C is a missense variant (p.Gly1166Arg); it does not fall into the default PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not a null variant.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/APS1 requires the same amino acid change via a different nucleotide substitution; no evidence of an alternative nucleotide change producing p.Gly1166Arg was identified. Details ▾Hide ▴
Evidence considered
  • No alternative nucleotide change yielding the same amino acid substitution was found.
PM3 N/APM3 applies to recessive disorders where the variant is observed 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 from in-frame deletions/insertions, stop-loss, or initiation codon variants; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo same-residue comparator variants (different missense change at Gly1166 classified as pathogenic) were identified in ClinVar. PM5 candidate harvesting returned zero candidates. Details ▾Hide ▴
Evidence considered
  • No pathogenic comparator at Gly1166 with a different amino acid substitution.
Sources
pm5_candidates
BP1 N/ANF1 is associated with numerous pathogenic missense variants; disease is not caused exclusively by truncating variants. Details ▾Hide ▴
Evidence considered
  • NF1 has many pathogenic missense variants across the gene.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants without splice impact; this is a missense variant (p.Gly1166Arg). Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
NF1
Transcript
NM_001042492.3
Coding (HGVS c.)
NM_001042492.3:c.3496G>C
Protein (HGVS p.)
NP_001035957.1:p.(Gly1166Arg)
GRCh38
chr17:31232881 G>C
GRCh37
chr17:29559899 G>C
ClinVar
1731988, 1359259

Gene diagram

Every interpreted variant in NF1, mapped onto the exon structure of NM_001042492.3. Select a row to find it on the plot.

NF1NM_001042492.3
Fetching transcript structure from UCSC…
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

SpliceAI acceptor lossat -181 bp
0.350
SpliceAI acceptor gainat +199 bp
0.000
SpliceAI donor lossat +0 bp
0.760
SpliceAI donor gainat -66 bp
0.030
Pangolin splice lossmagnitude shown
-0.710
Pangolin splice gain
0.010

Other predictors

REVEL
0.510
BayesDel
0.053

How the predictions were used

PP3 SupportingSpliceAI predicts a significant donor loss at the exon 26–intron 26 boundary (DS_DL = 0.76, well above the 0.2 threshold), consistent with the variant altering the last nucleotide of exon 26 (c.3496G>C at position −1 of the donor splice site). REVEL (0.51) is borderline; BayesDel (0.053) is below the pathogenic threshold. The SpliceAI donor loss prediction provides in silico support for a deleterious effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI delta score (donor loss) = 0.76
  • predicting disruption of the exon 26 donor splice site.
  • REVEL = 0.51 (borderline pathogenic).
  • BayesDel = 0.053 (below pathogenic threshold).
Still missing
  • Confirmation by RNA studies would strengthen the splice prediction.
Sources
spliceai ↗revelbayesdel
BP4 Multiple in silico tools predict a deleterious effect. SpliceAI predicts a donor loss with delta score 0.76. REVEL score (0.51) is borderline pathogenic. The evidence does not support a benign in silico consensus. Details ▾Hide ▴
Evidence considered
  • SpliceAI delta = 0.76 (donor loss
  • deleterious prediction).
  • REVEL = 0.51 (borderline
  • not clearly benign).
Sources
spliceai ↗revelbayesdel
BP7 N/ABP7 applies to synonymous variants without splice impact; this is a missense variant (p.Gly1166Arg). Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.76). REVEL score = 0.51. BayesDel score = 0.0531436.

2 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

  • Fifty-four novel mutations in the NF1 gene and integrated analyses of the mutations that modulate splicing.
    Xu W et al. · 2014
    Reports 127 different NF1 mutations including 54 novel mutations in a retrospective case series of 378 cases, with a focus on mutations that modulate splicing. NM_001042492.3:c.3496G>C was not identified among the reported variants.
    Does not name this variant
    PMID 24789688 ↗
  • 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. · 2015
    ACMG/NSGC practice guideline providing referral indications for cancer predisposition assessment. This is a general guideline document; no specific NF1 variants are discussed.
    Does not name this variant
    PMID 25394175 ↗

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 0.760 Open source ↗
ClinVar 1 Pathogenic · 1 Likely 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

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 Pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 1731988)

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.76). REVEL score = 0.51. BayesDel score = 0.0531436.

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.