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NF1c.7039G>TPathogenic
Print report
Variant interpretation report

NF1 c.7039G>T, p.(Glu2347Ter)

NM_000267.3:c.7039G>T NP_000258.1:p.(Glu2347Ter) View identifiers
Classification
Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

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 v1.0.0. 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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong

Nonsense variant NM_000267.3:c.7039G>T (p.Glu2347Ter) in exon 42 of 60 exons. NF1 loss-of-function is an established disease mechanism for neurofibromatosis type 1. The premature termination codon is located >50 nucleotides upstream of the last exon-exon junction, predicting nonsense-mediated decay. Per ClinGen SVI PVS1 recommendations (PMC6185798), nonsense variants in genes with an established LoF mechanism are assigned PVS1 at very_strong strength when NMD is predicted.

PM2Supporting
PM2 · supporting

NM_000267.3:c.7039G>T is absent from all queried population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Absence from large population cohorts supports pathogenicity.

PP5Supporting
PP5 · supporting

ClinVar reports this variant as Pathogenic by a clinical testing laboratory (GeneDx, SCV005333207). Although from a single submitter with criteria provided and no expert panel review, the clinical laboratory classification supports pathogenicity.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

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: PVS1 very strong, PM2 supporting, PP5 supporting; combination = 1 very strong + 2 supporting, which maps to Pathogenic.

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
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen NF1 VCEP v1.0.0, with the data and sources behind each one.

29 criteria with recorded statuses: 3 met · 17 not met · 0 not assessed · 9 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_000267.3:c.7039G>T (p.Glu2347Ter) is a nonsense variant in NF1 exon 42 of 60 exons. NF1 loss-of-function is an established disease mechanism for neurofibromatosis type 1. The premature termination codon is predicted to trigger nonsense-mediated decay, satisfying PVS1 at very_strong strength per ClinGen SVI PVS1 recommendations (PMC6185798).

The variant is absent from all population databases, including gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting PM2 at supporting strength.

ClinVar classifies this variant as Pathogenic (GeneDx, SCV005333207, criteria provided, single submitter), meeting PP5 at supporting strength.

Classification: Pathogenic. PVS1 (very_strong) plus PM2 (supporting) plus PP5 (supporting) satisfies the generic ACMG/AMP 2015 rule requiring 1 Very Strong and 2 Supporting criteria for a Pathogenic classification.

Met · 3

PVS1 Very strongNonsense variant NM_000267.3:c.7039G>T (p.Glu2347Ter) in exon 42 of 60 exons. NF1 loss-of-function is an established disease mechanism for neurofibromatosis type 1. The premature termination codon is located >50 nucleotides upstream of the last exon-exon junction, predicting nonsense-mediated decay. Per ClinGen SVI PVS1 recommendations (PMC6185798), nonsense variants in genes with an established LoF mechanism are assigned PVS1 at very_strong strength when NMD is predicted. Details ▾Hide ▴
Evidence considered
  • Nonsense variant p.Glu2347Ter in NF1 exon 42/60
  • NF1 loss-of-function is an established disease mechanism for neurofibromatosis type 1
  • PTC located >1400 nt upstream of final exon-exon junction
  • NMD predicted per PMC6185798
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 SupportingNM_000267.3:c.7039G>T is absent from all queried population databases, including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Absence from large population cohorts supports pathogenicity. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes)
  • Absent from gnomAD v4.1 (exomes)
  • Absent from gnomAD-Canada v1.0 (genomes)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP5 SupportingClinVar reports this variant as Pathogenic by a clinical testing laboratory (GeneDx, SCV005333207). Although from a single submitter with criteria provided and no expert panel review, the clinical laboratory classification supports pathogenicity. Details ▾Hide ▴
Evidence considered
  • ClinVar: Pathogenic
  • criteria provided
  • single submitter (GeneDx
  • SCV005333207)
Still missing
  • Single submitter
  • not expert panel reviewed
Sources
clinvar ↗

Not met · 17 · evaluated, threshold not reached

PS1 PS1 applies when a different nucleotide change at the same position produces the same amino acid change and is known to be pathogenic. This is a nonsense variant; no alternative nucleotide substitution at c.7039 producing the same stop codon is reported as pathogenic. Details ▾Hide ▴

No further detail was recorded.

PS2 No de novo confirmation with confirmed maternity/paternity is available for this variant in the reviewed evidence. Details ▾Hide ▴
Still missing
  • No family studies or de novo testing data available
PS3 No well-established functional studies demonstrate a damaging effect specific to NM_000267.3:c.7039G>T. OncoKB classifies the variant as Likely Oncogenic based on curated literature context, but none of the five OncoKB-linked publications (PMID:10543400, PMID:10862084, PMID:12509763, PMID:14722914, PMID:19573811) mention this specific variant. No variant-specific functional assay data are available. Details ▾Hide ▴
Evidence considered
  • OncoKB Likely Oncogenic classification notes likely loss-of-function context
Still missing
  • No variant-specific functional studies identified
Sources
oncokb ↗
PS4 No case-control prevalence data are available to demonstrate statistically significant enrichment of this variant in affected individuals compared to controls. Details ▾Hide ▴
Still missing
  • No case-control or prevalence studies available
PM1 This variant does not lie in a known mutational hotspot or critical functional domain as assessed by CancerHotspots.org. The variant is not in a statistically significant hotspot region. Details ▾Hide ▴
Evidence considered
  • CancerHotspots.org: no significant hotspot at this residue
PM6 No de novo observation (without confirmation of paternity/maternity) has been documented for this variant in the reviewed evidence. Details ▾Hide ▴
Still missing
  • No de novo reports identified
PP1 No co-segregation data in affected family members are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP4 No patient-specific phenotype or family history data are available to assess whether the individual's presentation is highly specific for NF1-related disease. Details ▾Hide ▴
Still missing
  • No patient phenotype data available
BA1 Allele frequency is well below 1% in all population databases. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • Absent from all population databases
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 Allele frequency is well below 0.3% in all population databases. The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
  • Absent from all population databases
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No data are available regarding observation of this variant in healthy adults in a homozygous or heterozygous state inconsistent with disease penetrance. Details ▾Hide ▴
Still missing
  • No healthy adult carrier data available
BS3 No well-established functional studies demonstrate no deleterious effect for this specific variant. The reviewed literature contains no variant-specific functional data for NM_000267.3:c.7039G>T. Details ▾Hide ▴
Still missing
  • No variant-specific functional studies available
BS4 No segregation data demonstrate lack of co-segregation with disease for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available
BP2 No data are available regarding observation of this variant in trans with a known pathogenic NF1 variant. Details ▾Hide ▴
Still missing
  • No trans-phase observation data available
BP5 No alternate molecular basis for disease has been identified that would make this variant irrelevant to the phenotype. Details ▾Hide ▴

No further detail was recorded.

BP6 ClinVar classifies this variant as Pathogenic. No reputable source reports this variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: Pathogenic
  • not benign
Sources
clinvar ↗
PS5 PS5 requires the same amino acid change as an established pathogenic variant via an alternative nucleotide change. No same-residue alternative nucleotide change producing p.Glu2347Ter has been identified as pathogenic in ClinVar or the reviewed literature. Details ▾Hide ▴

No further detail was recorded.

Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/ASkipped per task instructions. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASkipped per task instructions. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a different pathogenic missense change at the same residue. This is a nonsense variant; no same-residue pathogenic missense candidates suitable for PM5 were identified. Details ▾Hide ▴
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. This is a nonsense variant. Details ▾Hide ▴

No further detail was recorded.

PP3 N/APP3 applies to missense or splice-affecting variants with in silico support for a damaging effect. This is a nonsense variant; in silico missense predictors (REVEL, BayesDel) are not relevant to the truncating mechanism. SpliceAI predicts no splicing impact (max delta 0.02). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.02 (no splicing impact)
  • BayesDel score 0.652 (not applicable to nonsense variant)
Sources
spliceai ↗bayesdel
BP1 N/ABP1 applies to missense variants in genes where a truncating mechanism is the primary cause of disease. This is a nonsense (truncating) variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ASkipped per task instructions. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 applies to variants with multiple lines of in silico evidence suggesting no impact. This is a nonsense variant producing a premature termination codon; in silico missense predictors are not relevant. SpliceAI predicts no splicing impact (max delta 0.02), but the truncating effect supersedes this. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.02 (no splicing impact)
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants. c.7039G>T is a nonsense variant producing p.Glu2347Ter. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
NF1
Transcript
NM_000267.3
Coding (HGVS c.)
NM_000267.3:c.7039G>T
Protein (HGVS p.)
NP_000258.1:p.(Glu2347Ter)
GRCh38
chr17:31343048 G>T
GRCh37
chr17:29670066 G>T
ClinVar
3343861

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…
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 -39 bp
0.010
SpliceAI acceptor gainat -140 bp
0.010
SpliceAI donor lossat +87 bp
0.020
SpliceAI donor gainat +473 bp
0.000
Pangolin splice lossmagnitude shown
-0.240
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
0.653

How the predictions were used

PP3 N/APP3 applies to missense or splice-affecting variants with in silico support for a damaging effect. This is a nonsense variant; in silico missense predictors (REVEL, BayesDel) are not relevant to the truncating mechanism. SpliceAI predicts no splicing impact (max delta 0.02). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.02 (no splicing impact)
  • BayesDel score 0.652 (not applicable to nonsense variant)
Sources
spliceai ↗bayesdel
BP4 N/ABP4 applies to variants with multiple lines of in silico evidence suggesting no impact. This is a nonsense variant producing a premature termination codon; in silico missense predictors are not relevant. SpliceAI predicts no splicing impact (max delta 0.02), but the truncating effect supersedes this. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.02 (no splicing impact)
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants. c.7039G>T is a nonsense variant producing p.Glu2347Ter. 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

  • Evaluation of the protein truncation test and mutation detection in the NF1 gene: mutational analysis of 15 known and 40 unknown mutations.
    Evaluates the protein truncation test (PTT) for NF1 mutation detection in 15 patients with known mutations and 40 with unknown mutations. Reports 21 novel and previously described truncating mutations (nonsense, frameshift, splice). NM_000267.3:c.7039G>T was not among the variants identified.
    Does not name this variant
    PMID 10543400 ↗
  • Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects.
    Exhaustive mutation analysis of 67 unrelated NF1 patients using PTT, heteroduplex, FISH, Southern blot, and cytogenetics identifies mutations in 95% of cases (25 nonsense, 12 frameshift, 19 splice, 6 missense). NM_000267.3:c.7039G>T was not among the reported mutations.
    Does not name this variant
    PMID 10862084 ↗
  • Targeting RAS signalling pathways in cancer therapy.
    Review article on RAS signaling pathways in cancer therapy. Discusses NF1/neurofibromin as a RAS-GAP and tumor suppressor at the gene level. NM_000267.3:c.7039G>T is not mentioned in this review.
    Does not name this variant
    PMID 12509763 ↗
  • Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene.
    Screens 500 unselected NF1 patients for deletions of the NF1 gene using microsatellite markers and FISH. Identifies NF1 whole-gene deletions in 4.4% of patients. Does not report intragenic point mutations such as NM_000267.3:c.7039G>T.
    Does not name this variant
    PMID 14722914 ↗
  • Proteasomal and genetic inactivation of the NF1 tumor suppressor in gliomagenesis.
    Reports proteasomal and genetic inactivation of NF1 in sporadic gliomas. Demonstrates NF1 loss via proteasomal degradation and genetic deletion in glioblastoma. Does not report the specific germline variant NM_000267.3:c.7039G>T.
    Does not name this variant
    PMID 19573811 ↗

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 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

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

Error retrieving ClinVar entry.

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.