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NF1c.2325+16C>GLikely benign
Print report
Variant interpretation report

NF1 c.2325+16C>G, p.?

NM_000267.3:c.2325+16C>G NP_000258.1:p.? View identifiers
Classification
Likely benign

Variant description:

No variant summary was recorded for this case.

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

Likely benign.A likely benign 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: 1 Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_000267.3:c.2325+16C>G is observed at extremely low frequency in population databases: gnomAD v2.1 AF=0.00497% (14/281,840 alleles, 0 homozygotes) and gnomAD v4.1 AF=0.01147% (185/1,612,866 alleles, 0 homozygotes). Both frequencies are well below the 0.1% threshold.

Benign criteria applied · 2
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no significant splicing alteration (max delta score = 0.02). REVEL and BayesDel scores are not available for this intronic variant, but the SpliceAI prediction is consistent with a benign interpretation.

BP6Supporting
BP6 · supporting

NM_000267.3:c.2325+16C>G has been reported as Likely benign by 4 clinical testing laboratories in ClinVar (VariationID: 512450), including GeneDx, Athena Diagnostics, Genome-Nilou Lab, and Labcorp Genetics (formerly Invitae). All submissions are from reputable clinical diagnostic laboratories.

Recorded classification: Likely benign

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: PM2 supporting, BP4 supporting, BP6 supporting; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.

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
185 / 1,612,866 alleles

gnomAD v4.1: 185 / 1,612,866 alleles. Recorded AF 0.000114703. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.96736e-05; MAF= 0.00497%, 14/281840 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.34507e-05; MAF= 0.00935%, 12/128410 alleles, homozygotes = 0); grpmax FAF= 5.412e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.020 maximum delta

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

Applied · BP4 → SpliceAI ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
For specialists

Technical detail

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

26 criteria with recorded statuses: 3 met · 5 not met · 11 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000267.3:c.2325+16C>G is an intronic variant located 16 bases downstream of NF1 exon 19. SpliceAI predicts no significant splicing impact (max delta score = 0.02), and the variant is not expected to alter neurofibromin function.

This variant is observed at extremely low frequency in population databases: gnomAD v2.1 allele frequency 0.00497% (14/281,840 alleles) and gnomAD v4.1 allele frequency 0.01147% (185/1,612,866 alleles), with no homozygotes reported (PM2_Supporting).

Multiple lines of computational evidence predict no deleterious effect: SpliceAI delta score of 0.02 indicates no significant splice alteration, and no protein-level consequence is predicted for this deep intronic change (BP4).

This variant has been classified as Likely benign by 4 independent clinical diagnostic laboratories in ClinVar (VariationID: 512450), including GeneDx, Athena Diagnostics, Genome-Nilou Lab, and Labcorp Genetics (BP6).

Applying the ACMG/AMP 2015 combination rules (PMID:25741868): 1 supporting pathogenic criterion (PM2_Supporting) and 2 supporting benign criteria (BP4, BP6). The preponderance of benign evidence supports classification as Likely Benign.

Met · 3

PM2 SupportingNM_000267.3:c.2325+16C>G is observed at extremely low frequency in population databases: gnomAD v2.1 AF=0.00497% (14/281,840 alleles, 0 homozygotes) and gnomAD v4.1 AF=0.01147% (185/1,612,866 alleles, 0 homozygotes). Both frequencies are well below the 0.1% threshold. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: AF=0.00497% (14/281
  • 840)
  • gnomAD v4.1: AF=0.01147% (185/1
  • 612
  • 866)
  • no homozygotes.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no significant splicing alteration (max delta score = 0.02). REVEL and BayesDel scores are not available for this intronic variant, but the SpliceAI prediction is consistent with a benign interpretation. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02
  • no predicted donor/acceptor gain or loss.
Sources
spliceai ↗
BP6 SupportingNM_000267.3:c.2325+16C>G has been reported as Likely benign by 4 clinical testing laboratories in ClinVar (VariationID: 512450), including GeneDx, Athena Diagnostics, Genome-Nilou Lab, and Labcorp Genetics (formerly Invitae). All submissions are from reputable clinical diagnostic laboratories. Details ▾Hide ▴
Evidence considered
  • ClinVar: Likely benign (4 clinical laboratories — GeneDx
  • Athena Diagnostics
  • Genome-Nilou Lab
  • Labcorp Genetics).
Sources
clinvar ↗

Not met · 5 · evaluated, threshold not reached

PM1 The variant is not located in a known mutational hotspot or critical functional domain. Hotspot analysis shows residue_significant=false and exact_variant_listed=no. Details ▾Hide ▴
Evidence considered
  • Not located in a recognized NF1 mutational hotspot or critical functional domain.
PP3 Multiple in silico tools do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta score = 0.02). REVEL and BayesDel scores are not available for this intronic variant. HCI prior is not available for NF1. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02 (no splice impact)
  • REVEL/BayesDel/HCI not available.
Sources
spliceai ↗
PP5 ClinVar reports NM_000267.3:c.2325+16C>G as Likely benign by 4 clinical testing laboratories (GeneDx, Athena Diagnostics, Genome-Nilou Lab, Labcorp Genetics). No reputable source reports this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Likely benign (4 submitters)
  • no submitter reports pathogenic.
Sources
clinvar ↗
BA1 The highest population allele frequency is 0.01147% (gnomAD v4.1), well below the 1% threshold for BA1. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=0.01147%
  • gnomAD v2.1 AF=0.00497%
  • both far below 1%.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The highest population allele frequency is 0.01147% (gnomAD v4.1), which is below the 0.3% threshold for BS1. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=0.01147%
  • gnomAD v2.1 AF=0.00497%
  • both below 0.3%.
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not assessed · 11 · no assessment recorded

PS2 No de novo occurrence data were identified for NM_000267.3:c.2325+16C>G in the available literature or ClinVar submissions. Details ▾Hide ▴
Still missing
  • No de novo reports identified in literature or databases.
PS3 No functional studies were identified for NM_000267.3:c.2325+16C>G. The three full-text publications reviewed (PMID:25741868, PMID:26467025, PMID:20065170) do not mention this variant, and no other functional data are available. Details ▾Hide ▴
Still missing
  • No variant-specific functional studies available.
PS4 No case-control or case-series data were identified for NM_000267.3:c.2325+16C>G. The variant is present in gnomAD at low frequency and has been observed in clinical testing but without case-level detail. Details ▾Hide ▴
Still missing
  • No case-control studies or case series available for this variant.
PM6 No confirmed de novo occurrence data were identified for NM_000267.3:c.2325+16C>G in ClinVar submissions or the available literature. Details ▾Hide ▴
Still missing
  • No de novo reports identified.
PP1 No segregation data are available for NM_000267.3:c.2325+16C>G in the literature or ClinVar submissions. Details ▾Hide ▴
Still missing
  • No co-segregation data available.
PP4 No phenotype or family history data specific to NM_000267.3:c.2325+16C>G are available in the literature or ClinVar submissions. Details ▾Hide ▴
Still missing
  • No phenotype-specific data available.
BS2 No data are available regarding observation of NM_000267.3:c.2325+16C>G in healthy adults in the absence of NF1-related features. Details ▾Hide ▴
Still missing
  • No data on observation in healthy adults without NF1.
BS3 No functional studies demonstrating a benign effect were identified for NM_000267.3:c.2325+16C>G. The SpliceAI delta score of 0.02 suggests no splicing impact but is assessed under BP4 rather than BS3. Details ▾Hide ▴
Still missing
  • No variant-specific functional studies available.
BS4 No segregation data are available to evaluate lack of segregation with disease for NM_000267.3:c.2325+16C>G. Details ▾Hide ▴
Still missing
  • No segregation data available.
BP2 No data are available regarding observation of NM_000267.3:c.2325+16C>G in trans with a known pathogenic NF1 variant. Details ▾Hide ▴
Still missing
  • No data on observation in trans with pathogenic variant.
BP5 No data are available regarding an alternative molecular basis for disease in individuals carrying NM_000267.3:c.2325+16C>G. Details ▾Hide ▴
Still missing
  • No data on alternative molecular diagnoses.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000267.3:c.2325+16C>G is an intronic variant located 16 bases downstream of exon 19. It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants, and the ClinGen SVI PVS1 framework (PMC6185798) does not apply. Details ▾Hide ▴
Evidence considered
  • Intronic variant at +16 position
  • canonical_splice_consensus=false
  • variant_bucket=other
  • generic PVS1 framework not applicable.
Sources
pvs1_variant_assessment
PS1 N/APS1 applies when a variant produces the same amino acid change as a known pathogenic variant. NM_000267.3:c.2325+16C>G is intronic and does not alter the protein coding sequence. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • no amino acid change.
PM5 N/AUnable to confirm classic same-residue PM5 semantics. The variant is intronic and does not produce a missense change; no residue context can be determined for comparator analysis. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • no amino acid residue
  • PM5 candidate harvesting not feasible.
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes where missense variants are a common mechanism of disease and benign missense variation is rare. NM_000267.3:c.2325+16C>G is intronic and not a missense change. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • not a missense change.
BP1 N/ABP1 applies to missense variants in genes where a truncating mechanism is predominant. NM_000267.3:c.2325+16C>G is intronic and not a missense change. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • not a missense change.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_000267.3:c.2325+16C>G is an intronic variant, not a synonymous coding change. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • not synonymous.
PS5 N/APS5 applies to missense variants at a residue where a different missense change is known to be pathogenic. NM_000267.3:c.2325+16C>G is intronic and does not alter the protein coding sequence. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • no amino acid residue affected.

Identifiers

Gene
NF1
Transcript
NM_000267.3
Coding (HGVS c.)
NM_000267.3:c.2325+16C>G
Protein (HGVS p.)
NP_000258.1:p.?
GRCh38
chr17:31227307 C>G
GRCh37
chr17:29554325 C>G
ClinVar
512450

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 v4.1 185 / 1,612,866 alleles AF 0.000115 · 0 homozygotes · FAF 0.000136
gnomAD v2.1 14 / 281,840 alleles AF 4.97e-05 · 0 homozygotes · FAF 5.41e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.00011 · 185 / 1,612,866 alleles · 0 hom · FAF 0.00014
European (non-Finnish)182 / 1,179,034 0.00015
African/African American2 / 74,872 2.7e-05
Remaining individuals1 / 62,438 1.6e-05
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 5e-05 · 14 / 281,840 alleles · 0 hom · FAF 5.4e-05
European (non-Finnish)12 / 128,410 9.3e-05
African/African American2 / 24,862 8e-05
0 alternate alleles recorded in 6 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.000114703; MAF= 0.01147%, 185/1612866 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000154364; MAF= 0.01544%, 182/1179034 alleles, homozygotes = 0); grpmax FAF= 0.00013594.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.96736e-05; MAF= 0.00497%, 14/281840 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.34507e-05; MAF= 0.00935%, 12/128410 alleles, homozygotes = 0); grpmax FAF= 5.412e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -85 bp
0.020
SpliceAI acceptor gainat -26 bp
0.000
SpliceAI donor lossat -16 bp
0.020
SpliceAI donor gainat +106 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no significant splicing alteration (max delta score = 0.02). REVEL and BayesDel scores are not available for this intronic variant, but the SpliceAI prediction is consistent with a benign interpretation. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02
  • no predicted donor/acceptor gain or loss.
Sources
spliceai ↗
PP3 Multiple in silico tools do not support a deleterious effect. SpliceAI predicts no significant splice impact (max delta score = 0.02). REVEL and BayesDel scores are not available for this intronic variant. HCI prior is not available for NF1. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.02 (no splice impact)
  • REVEL/BayesDel/HCI not available.
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_000267.3:c.2325+16C>G is an intronic variant, not a synonymous coding change. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

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

  • 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.
    This is the ACMG/AMP standards and guidelines for sequence variant interpretation. The paper establishes the generic classification framework and combination rules but does not discuss any specific NF1 variants. NM_000267.3:c.2325+16C>G was not identified in this publication.
    Does not name this variant
    PMID 25741868 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    This paper describes a standardized DNA variant scoring system (Sherloc precursor) for pathogenicity assessment in Mendelian disorders. It analyzes over 16,500 variant assessments across 338 genes but does not discuss NM_000267.3:c.2325+16C>G or any specific NF1 intronic variant.
    Does not name this variant
    PMID 26467025 ↗
  • American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.
    Robson ME et al. · 2010
    This is an ASCO policy statement on genetic and genomic testing for cancer susceptibility. It discusses general principles of germline testing, clinical utility, and direct-to-consumer testing but does not mention NF1 or any specific NF1 variant. NM_000267.3:c.2325+16C>G was not identified in this publication.
    Does not name this variant
    PMID 20065170 ↗
  • Neurofibromatosis 1.
    Adam MP et al. · 1993
    This is a GeneReviews chapter on Neurofibromatosis type 1. It provides a general overview of NF1 clinical features, diagnosis, and management but does not discuss individual variants. NM_000267.3:c.2325+16C>G was not identified in this publication.
    Does not name this variant
    PMID 20301288 ↗
  • Wilms Tumor Predisposition.
    Adam MP et al. · 1993
    This is a GeneReviews chapter on Wilms Tumor Predisposition. It does not discuss NF1 or NF1 variants. NM_000267.3:c.2325+16C>G was not identified in this publication.
    Does not name this variant
    PMID 20301471 ↗
  • Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents.
    Botkin JR et al. · 2015
    This paper discusses ethical, legal, and psychosocial implications of genetic testing in children and adolescents. It does not discuss NF1 or any specific NF1 variants. NM_000267.3:c.2325+16C>G was not identified in this publication.
    Does not name this variant
    PMID 26140447 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    This paper presents the Sherloc refinement of ACMG-AMP variant classification criteria. It provides a general classification framework but does not discuss any specific NF1 variants. NM_000267.3:c.2325+16C>G was not identified in this publication.
    Does not name this variant
    PMID 28492532 ↗
  • The North American Neuroendocrine Tumor Society Consensus Guidelines for Surveillance and Management of Metastatic and/or Unresectable Pheochromocytoma and Paraganglioma.
    Fishbein L et al. · 2021
    This paper provides NANETS consensus guidelines for surveillance and management of pheochromocytoma and paraganglioma. It does not discuss NF1 variants. NM_000267.3:c.2325+16C>G was not identified in this publication.
    Does not name this variant
    PMID 33939658 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 185 / 1,612,866 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar 4 Likely benign Open source ↗
COSMIC Captured COSMIC 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

This variant is present in gnomAD v4.1 (AF= 0.000114703; MAF= 0.01147%, 185/1612866 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000154364; MAF= 0.01544%, 182/1179034 alleles, homozygotes = 0); grpmax FAF= 0.00013594.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.96736e-05; MAF= 0.00497%, 14/281840 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.34507e-05; MAF= 0.00935%, 12/128410 alleles, homozygotes = 0); grpmax FAF= 5.412e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (4 clinical laboratories). (ClinVarID = 512450)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).