About NF1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NF1 c.4661+11A>G, p.?
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.
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: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BS3Supporting
BS3 · supporting
Wimmer et al. (2007) performed a minigene splicing assay demonstrating normal splicing of c.4661+11A>G with no exon skipping or cryptic splice site activation. This well-established functional assay provides evidence that the variant does not impair mRNA splicing, supporting a benign effect. Note: this finding was identified through exploratory analysis and should be verified by reviewing the full text of PMID:17295913.
BP4Supporting
BP4 · supporting
SpliceAI predicts no significant splice impact (max delta score = 0.10). REVEL and BayesDel are not applicable for this intronic variant. The available computational evidence does not support a deleterious splicing effect.
BP6Supporting
BP6 · supporting
Multiple clinical diagnostic laboratories (4 of 7 usable submissions) classify this variant as Likely benign in ClinVar. The majority consensus among clinical testing laboratories provides reputable source evidence supporting a benign interpretation.
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: BS3 supporting benign, BP4 supporting benign, BP6 supporting benign; combination = 3 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
281 / 1,612,590 alleles
gnomAD v4.1: 281 / 1,612,590 alleles. Recorded AF 0.000174254. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.78866e-05; MAF= 0.00779%, 22/282462 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00015514; MAF= 0.01551%, 20/128916 alleles, homozygotes = 0); grpmax FAF= 0.00010881.
No listed criterion applied
SpliceAI score
0.100 maximum delta
Recorded SpliceAI maximum delta score: 0.100. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
7 reported laboratory submissions
4 Likely benign · 3 Uncertain significance.
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
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.
27 criteria with recorded statuses: 3 met · 11 not met · 5 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
NM_000267.3:c.4661+11A>G is an intronic variant in NF1 (intron 34, +11 position) that has been observed in population databases at low frequency (gnomAD v2.1: 22/282,462 alleles, AF=0.0078%; v4.1: 281/1,612,590 alleles, AF=0.0174%).
Computational splicing prediction (SpliceAI, max delta = 0.10) indicates no significant impact on mRNA splicing.
A minigene splicing assay (Wimmer et al. 2007, PMID:17295913) demonstrated normal splicing of this variant with no exon skipping or cryptic splice site activation, providing functional evidence against a deleterious splicing effect (BS3_Supporting).
Multiple clinical laboratories in ClinVar classify this variant as Likely benign (4 of 7 usable submissions), with no pathogenic classifications reported (BP6_Supporting).
No pathogenic criteria are met. PVS1 is not applicable as this non-canonical intronic variant does not produce a null allele. PM2 is not met as the variant is present above absence thresholds. PS4 is not met due to population frequency inconsistent with a rare fully penetrant disorder. PS3 is not met as the only functional study shows normal splicing.
Based on the available evidence (BS3_Supporting, BP4_Supporting, BP6_Supporting), this variant meets criteria for Likely benign classification. Note: BS3 is from a single minigene assay requiring verification; BP4 is from SpliceAI computational prediction; BP6 is from ClinVar clinical laboratory consensus without expert panel review.
No criteria match.
Met · 3
BS3 SupportingWimmer et al. (2007) performed a minigene splicing assay demonstrating normal splicing of c.4661+11A>G with no exon skipping or cryptic splice site activation. This well-established functional assay provides evidence that the variant does not impair mRNA splicing, supporting a benign effect. Note: this finding was identified through exploratory analysis and should be verified by reviewing the full text of PMID:17295913. Details ▾Hide ▴
Evidence considered
- Minigene splicing assay demonstrated normal splicing (Wimmer et al. 2007
- PMID:17295913)
- No aberrant splicing or cryptic splice site activation detected
Still missing
- PMID:17295913 full text not available for direct verification in this case
- Only one functional assay published
- replication would strengthen conclusion
Sources
17295913
BP4 SupportingSpliceAI predicts no significant splice impact (max delta score = 0.10). REVEL and BayesDel are not applicable for this intronic variant. The available computational evidence does not support a deleterious splicing effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.10 (below commonly applied thresholds for splice-altering prediction)
Sources
BP6 SupportingMultiple clinical diagnostic laboratories (4 of 7 usable submissions) classify this variant as Likely benign in ClinVar. The majority consensus among clinical testing laboratories provides reputable source evidence supporting a benign interpretation. Details ▾Hide ▴
Evidence considered
- ClinVar: 4 Likely benign classifications from clinical laboratories
- 3 Uncertain significance classifications
- No pathogenic classifications
Still missing
- No expert panel review in ClinVar
- all submissions are single-submitter
Sources
Not met · 11 · evaluated, threshold not reached
PS2 No confirmed de novo occurrence with maternity and paternity testing has been reported in the literature for this variant. Details ▾Hide ▴
Evidence considered
- No published report of de novo occurrence with confirmed parentage found
Still missing
- No de novo case with confirmed parentage identified
PS3 The only functional study identified (Wimmer et al. 2007, PMID:17295913) demonstrated normal splicing in a minigene assay, indicating no damaging effect on mRNA processing. No in vitro or in vivo studies have demonstrated a deleterious functional impact. Details ▾Hide ▴
Evidence considered
- Minigene assay showed normal splicing (PMID:17295913)
- No other functional studies demonstrating damaging effect
Still missing
- No functional evidence supporting a pathogenic effect
PS4 Although LOVD entries report multiple probands with NF1 carrying this variant, the variant is also observed in population databases at frequencies inconsistent with a fully penetrant rare disease allele (gnomAD v2.1: 22/282,462; v4.1: 281/1,612,590). The variant's prevalence in the general population precludes statistically significant enrichment in affected individuals. Details ▾Hide ▴
Evidence considered
- Variant present in gnomAD (v2.1 AF=0.0078%
- v4.1 AF=0.0174%)
- Population frequency exceeds expectation for a highly penetrant autosomal dominant disorder
Still missing
- No formal case-control comparison performed
Sources
PM1 This intronic +11 position in intron 34 is not located in a well-established mutational hotspot or critical functional domain of NF1. Details ▾Hide ▴
Evidence considered
- Intron 34 +11 is not a recognized NF1 mutational hotspot
Still missing
- No domain-level annotation supports this as a critical region
PM2 The variant is present in gnomAD at an allele frequency of 0.0078% (v2.1, 22/282,462 alleles) to 0.0174% (v4.1, 281/1,612,590 alleles), which exceeds the PM2 absence threshold (<0.1%) for a rare disease variant. The variant is observed across multiple subpopulations and in both exome and genome data. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 22/282
- 462 alleles (AF=0.0078%)
- gnomAD v4.1: 281/1
- 612
- 590 alleles (AF=0.0174%)
- 0 homozygotes in both datasets
Sources
PP3 SpliceAI predicts no significant splice impact (max delta score = 0.10). REVEL and BayesDel are not available for this intronic variant. No in silico tools support a deleterious effect on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.10 (no significant splice impact predicted)
- REVEL and BayesDel not applicable for intronic variants
Sources
PP5 No reputable source has recently reported this variant as pathogenic. ClinVar shows a consensus classification of Likely benign (4 clinical laboratories) and Uncertain significance (3 clinical laboratories). No ClinVar submission classifies this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: 4 Likely benign
- 3 Uncertain significance
- 0 Pathogenic submissions
- No expert panel classification available
Sources
BA1 The maximum allele frequency in gnomAD is 0.0227% (v4.1 European non-Finnish), which is well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpopulation AF = 0.0227% (European non-Finnish)
- gnomAD v2.1 max subpopulation AF = 0.0155% (European non-Finnish)
- BA1 threshold >1% not met
Sources
BS1 The maximum allele frequency in gnomAD is 0.0227% (v4.1 European non-Finnish), which is below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 max subpopulation AF = 0.0227%
- BS1 threshold >0.3% not met
Sources
BP2 No evidence of this variant occurring in trans with a known pathogenic NF1 variant has been reported. Given the autosomal dominant inheritance of NF1, such an observation would provide strong evidence for benignity but has not been documented. Details ▾Hide ▴
Evidence considered
- No reports of variant in trans with a pathogenic NF1 variant
Still missing
- No co-occurrence data available
BP5 No observation of this variant in a case where an alternative molecular basis for disease has been identified. Details ▾Hide ▴
Evidence considered
- No cases with alternative molecular diagnosis reported
Still missing
- No data on alternative molecular diagnoses in carriers
Not assessed · 5 · no assessment recorded
PM6 Exploratory search identified LOVD entries suggesting at least one apparently de novo occurrence without confirmed parentage. However, this could not be independently verified through the available case materials. Direct review of the LOVD database records is required before PM6 can be applied. Details ▾Hide ▴
Evidence considered
- LOVD reportedly contains entries with apparently de novo status (exploratory finding
- unverified)
Still missing
- Requires direct verification of LOVD de novo entries and parentage confirmation status
PP1 Exploratory search identified LOVD entries suggesting co-segregation in two small families. However, no published segregation analysis with statistical support was available for review. The variant is also observed in unaffected population controls, complicating segregation interpretation. Details ▾Hide ▴
Evidence considered
- LOVD reportedly contains two families with possible co-segregation (exploratory finding
- unverified)
Still missing
- No published segregation study with statistical analysis
- Variant present in gnomAD population controls
- Requires direct verification of LOVD segregation entries
PP4 No patient-specific phenotypic data were provided with this case. Cannot assess whether the patient's phenotype or family history is highly specific for NF1. Details ▾Hide ▴
Evidence considered
- No patient phenotype data available
Still missing
- Patient phenotype and family history information not provided
BS2 While the variant is observed in gnomAD at frequencies that suggest some carriers may be healthy adults (281 alleles in v4.1, with NF1 being nearly 100% penetrant by early childhood), gnomAD does not provide health status confirmation of carriers. Without documented observation in confirmed healthy adult individuals, BS2 cannot be formally applied. Details ▾Hide ▴
Evidence considered
- Variant present in 281/1
- 612
- 590 gnomAD v4.1 alleles (some carriers likely healthy adults given NF1 penetrance)
- No documented observation of variant in confirmed healthy adults
Still missing
- No direct confirmation that gnomAD carriers are healthy adults
Sources
BS4 Exploratory search identified a ClinVar submission (reportedly variation 428109) suggesting inheritance from an unaffected parent. However, this ClinVar variation ID differs from the primary variation for this variant (227742) and could not be independently verified. The submission provenance and the clinical certainty of the parent's unaffected status require direct review. Details ▾Hide ▴
Evidence considered
- Exploratory finding of possible non-segregation (unverified ClinVar submission)
Still missing
- Unable to verify ClinVar variation 428109 submission details
- Parental clinical status confirmation needed
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is an intronic variant at position +11, which does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The ClinGen SVI PVS1 decision tree does not apply to non-canonical intronic variants without demonstrated splicing aberration. A minigene assay demonstrated normal splicing (PMID:17295913), further confirming no null effect. Details ▾Hide ▴
Evidence considered
- Intronic variant at +11 position
- not a canonical splice site variant
- No protein-level consequence predictable from variant type
- Minigene assay shows normal splicing (PMID:17295913)
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ANo amino acid change; intronic variant does not produce a missense alteration at a residue with a known pathogenic missense variant. Details ▾Hide ▴
Evidence considered
- Intronic variant produces no amino acid change
PM5 N/ANo amino acid change; intronic variant has no residue context for same-residue comparator analysis. The pm5_candidates pipeline confirmed inability to parse missense residue context from the normalized protein consequence. Details ▾Hide ▴
Evidence considered
- Intronic variant
- no amino acid residue context available
Sources
pm5_candidates
PP2 N/AThis is an intronic variant, not a missense variant. PP2 applies only to missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- Intronic variant
- not a missense alteration
BP1 N/AThis is an intronic variant. BP1 applies specifically to missense variants in genes where a truncating mechanism causes disease. Details ▾Hide ▴
Evidence considered
- Intronic variant
- not a missense alteration
BP3 N/ASkipped — this is an intronic substitution, not an in-frame indel in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is an intronic variant at position +11, not a synonymous coding variant. While SpliceAI predicts no splice impact, the criterion is not directly applicable to deep intronic variants. Details ▾Hide ▴
Evidence considered
- Intronic variant
- BP7 is specified for synonymous variants
PS5 N/ANo amino acid change; intronic variant does not create a missense change at a residue with a known pathogenic missense variant. Details ▾Hide ▴
Evidence considered
- Intronic variant produces no amino acid change
Identifiers
- Gene
- NF1
- Transcript
- NM_000267.3
- Coding (HGVS c.)
- NM_000267.3:c.4661+11A>G
- Protein (HGVS p.)
- NP_000258.1:p.?
- GRCh38
- chr17:31261868 A>G
- GRCh37
- chr17:29588886 A>G
- ClinVar
- 227742
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
281 / 1,612,590 alleles
AF 0.000174 · 0 homozygotes · FAF 0.000205
gnomAD v2.1
22 / 282,462 alleles
AF 7.79e-05 · 0 homozygotes · FAF 0.000109
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 0.00017 · 281 / 1,612,590 alleles · 0 hom · FAF 0.0002
| European (non-Finnish)268 / 1,179,810 | 0.00023 |
| Remaining individuals6 / 62,356 | 9.6e-05 |
| African/African American6 / 74,876 | 8e-05 |
| European (Finnish)1 / 64,024 | 1.6e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 7.8e-05 · 22 / 282,462 alleles · 0 hom · FAF 0.00011
| European (non-Finnish)20 / 128,916 | 0.00016 |
| Remaining individuals1 / 7,204 | 0.00014 |
| African/African American1 / 24,962 | 4e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000174254; MAF= 0.01743%, 281/1612590 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000227155; MAF= 0.02272%, 268/1179810 alleles, homozygotes = 0); grpmax FAF= 0.00020451.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.78866e-05; MAF= 0.00779%, 22/282462 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00015514; MAF= 0.01551%, 20/128916 alleles, homozygotes = 0); grpmax FAF= 0.00010881.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingSpliceAI predicts no significant splice impact (max delta score = 0.10). REVEL and BayesDel are not applicable for this intronic variant. The available computational evidence does not support a deleterious splicing effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.10 (below commonly applied thresholds for splice-altering prediction)
Sources
PP3 SpliceAI predicts no significant splice impact (max delta score = 0.10). REVEL and BayesDel are not available for this intronic variant. No in silico tools support a deleterious effect on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.10 (no significant splice impact predicted)
- REVEL and BayesDel not applicable for intronic variants
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is an intronic variant at position +11, not a synonymous coding variant. While SpliceAI predicts no splice impact, the criterion is not directly applicable to deep intronic variants. Details ▾Hide ▴
Evidence considered
- Intronic variant
- BP7 is specified for synonymous variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
12 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 24033266 ↗A systematic approach to assessing the clinical significance of genetic variants.No paper-specific finding is recorded.
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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.No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
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PMID 17636453 ↗Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors.Radtke HB et al. · 2007No paper-specific finding is recorded.
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PMID 20065170 ↗American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.Robson ME et al. · 2010No paper-specific finding is recorded.
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PMID 20301288 ↗Neurofibromatosis 1.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 20301471 ↗Wilms Tumor Predisposition.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 20664475 ↗The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer.Chen H et al. · 2010No paper-specific finding is recorded.
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PMID 24893135 ↗Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.Lenders JW et al. · 2014No paper-specific finding is recorded.
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PMID 26140447 ↗Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents.Botkin JR et al. · 2015No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
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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.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
281 / 1,612,590 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.100
Open source ↗
ClinVar
4 Likely benign · 3 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC 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/227742/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-29588886-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-31261868-A-G?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000267.3%3Ac.4661…
- OncoKB ↗www.oncokb.org/gene/NF1/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NF1+c.4661+11A%3EG
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= 0.000174254; MAF= 0.01743%, 281/1612590 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000227155; MAF= 0.02272%, 268/1179810 alleles, homozygotes = 0); grpmax FAF= 0.00020451.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.78866e-05; MAF= 0.00779%, 22/282462 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00015514; MAF= 0.01551%, 20/128916 alleles, homozygotes = 0); grpmax FAF= 0.00010881.
ClinVar
Error retrieving ClinVar entry.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).