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NF1c.4270-9A>TLikely benign
Print report
Variant interpretation report

NF1 c.4270-9A>T, p.?

NM_000267.3:c.4270-9A>T 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

The variant is absent from gnomAD v2.1 and extremely rare in gnomAD v4.1 (7/1,541,860 alleles, AF = 4.54e-6, 0.00045%, all in European non-Finnish population, no homozygotes). The population frequency is well below the 0.1% threshold for PM2_supporting.

Benign criteria applied · 2
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no splicing alteration (max delta score = 0.00, with all four delta scores at 0.00: acceptor gain 0.00, acceptor loss 0.00, donor gain 0.00, donor loss 0.00). The variant is deep intronic and is not predicted to disrupt the native splice site.

BP6Supporting
BP6 · supporting

A reputable clinical testing laboratory (Labcorp Genetics, formerly Invitae) has classified this variant as Likely benign in ClinVar (Variation ID: 849602). Although the underlying evidence is not publicly available for independent evaluation, the classification from a clinical diagnostic laboratory with criteria provided supports a benign interpretation per BP6_supporting.

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.

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. 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 · 16 not met · 0 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.4270-9A>T is an intronic substitution located at position -9 of the intron 32 splice acceptor site in NF1.

The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (7/1,541,860 alleles, AF = 0.00045%, no homozygotes), satisfying PM2_supporting.

SpliceAI predicts no splicing impact (max delta score = 0.00), supporting BP4_supporting.

A reputable clinical laboratory (Labcorp Genetics/Invitae) has classified this variant as Likely benign in ClinVar (Variation ID: 849602), satisfying BP6_supporting.

No pathogenic criteria were met. PVS1 is not applicable as the variant is outside canonical splice sites and SpliceAI predicts no impact. No de novo (PS2/PM6), functional (PS3/BS3), segregation (PP1/BS4), or case-control (PS4) evidence was identified for this variant.

With three supporting benign criteria (PM2_supporting, BP4_supporting, BP6_supporting) and no pathogenic criteria met, the variant is classified as Likely Benign per generic ACMG/AMP 2015 combination rules.

Met · 3

PM2 SupportingThe variant is absent from gnomAD v2.1 and extremely rare in gnomAD v4.1 (7/1,541,860 alleles, AF = 4.54e-6, 0.00045%, all in European non-Finnish population, no homozygotes). The population frequency is well below the 0.1% threshold for PM2_supporting. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: absent
  • gnomAD v4.1: 7/1
  • 541
  • 860 alleles
  • AF = 4.54e-6 (0.00045%)
  • grpmax FAF = 2.6e-6
  • 0 homozygotes
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product. SpliceAI predicts no splicing alteration (max delta score = 0.00, with all four delta scores at 0.00: acceptor gain 0.00, acceptor loss 0.00, donor gain 0.00, donor loss 0.00). The variant is deep intronic and is not predicted to disrupt the native splice site. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.00 (all four delta positions at 0.00)
  • No computational prediction of splicing impact
Sources
spliceai ↗
BP6 SupportingA reputable clinical testing laboratory (Labcorp Genetics, formerly Invitae) has classified this variant as Likely benign in ClinVar (Variation ID: 849602). Although the underlying evidence is not publicly available for independent evaluation, the classification from a clinical diagnostic laboratory with criteria provided supports a benign interpretation per BP6_supporting. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 849602: Likely benign
  • criteria provided
  • single submitter (Labcorp Genetics/Invitae
  • accession SCV001217878)
Sources
clinvar ↗

Not met · 16 · evaluated, threshold not reached

PS2 No de novo occurrence of NM_000267.3:c.4270-9A>T has been reported with confirmed paternity and maternity. De novo databases and ClinVar show no de novo assertions for this variant. Details ▾Hide ▴
Evidence considered
  • Exploratory evidence search found no de novo reports for this variant
Still missing
  • No de novo observation with confirmed parentage
PS3 No well-established in vitro or in vivo functional studies have been identified that demonstrate a damaging effect of c.4270-9A>T on the gene or gene product. No minigene splicing assays, RNA studies, or protein functional data are available for this exact variant. Details ▾Hide ▴
Evidence considered
  • Exploratory evidence search found no functional assay results for this variant
Still missing
  • No functional study data for this variant
PS4 No case-control studies have demonstrated that the prevalence of c.4270-9A>T is significantly increased in affected individuals compared to controls. The variant is extremely rare in population databases (gnomAD v4.1 AF = 0.00045%), but this alone does not satisfy the case-control enrichment required for PS4. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 7/1
  • 541
  • 860 alleles
  • AF = 4.54e-6
  • No case-control enrichment data available
Still missing
  • No case-control data comparing variant prevalence in NF1-affected vs controls
Sources
gnomad_v4 ↗
PM1 The variant is located in intron 32, not within a known mutational hotspot or critical functional domain of neurofibromin. PM1 requires location in a mutational hotspot and/or critical and well-established functional domain without benign variation. Details ▾Hide ▴
Evidence considered
  • Intronic variant outside known NF1 mutational hotspots or functional domains
Still missing
  • Variant is deep intronic
  • not in a recognized hotspot
PM6 No de novo observation (even without confirmation of paternity/maternity) has been reported for c.4270-9A>T in ClinVar, LOVD, or the published literature. No de novo assertions were identified for this variant. Details ▾Hide ▴
Evidence considered
  • Exploratory evidence search found no de novo reports for this variant
Still missing
  • No de novo observation (assumed or confirmed)
PP1 No co-segregation data with disease in multiple affected family members has been reported for this variant. PP1 requires the variant to segregate with the phenotype in multiple affected family members across generations or in multiple affected siblings. Details ▾Hide ▴
Evidence considered
  • No co-segregation data available for this variant
Still missing
  • No family co-segregation data
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). REVEL and BayesDel are not available for this intronic variant. No in silico tools predict a damaging consequence. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.00 (acceptor gain 0.00
  • acceptor loss 0.00
  • donor gain 0.00
  • donor loss 0.00)
  • REVEL: not available (intronic)
  • BayesDel: not available (intronic)
Still missing
  • No missense-level in silico scores (REVEL/BayesDel) available for intronic variant
Sources
spliceai ↗
PP4 The variant has been submitted to ClinVar by a single clinical laboratory, but the specific phenotype and clinical details of the proband are not available. PP4 requires that the variant is identified in an individual with a phenotype highly specific for the disease. Details ▾Hide ▴
Evidence considered
  • ClinVar submission by Labcorp Genetics (Invitae) with Likely benign classification
  • No specific clinical phenotype details available for the proband
Still missing
  • No detailed phenotype information available for the individual(s) carrying this variant
Sources
clinvar ↗
PP5 The ClinVar classification for this variant is Likely benign (not pathogenic). The 12 PMIDs associated with the ClinVar entry are general clinical practice guidelines and review articles that do not mention the specific variant NM_000267.3:c.4270-9A>T. None of the cited publications contain variant-specific evidence to support a pathogenic assertion. Details ▾Hide ▴
Evidence considered
  • ClinVar classification: Likely benign (not pathogenic)
  • 12 associated PMIDs reviewed: none mention c.4270-9A>T
Still missing
  • No reputable source classifies this variant as pathogenic
Sources
clinvar ↗156046281763645320065170203012882030147120664475248931352614044726324357284925323260215333939658
BA1 The variant allele frequency in gnomAD v4.1 is 4.54e-6 (0.00045%), which is far below the BA1 threshold of greater than 1% (excludes benign standing in the population). Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 4.54e-6 (0.00045%)
  • well below 1% BA1 cutoff
Sources
gnomad_v4 ↗
BS1 The variant allele frequency in gnomAD v4.1 is 4.54e-6 (0.00045%), which is below the BS1 threshold of greater than 0.3% (allele frequency greater than expected for disorder). The variant is too rare to support BS1. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 4.54e-6 (0.00045%)
  • below 0.3% BS1 cutoff
Sources
gnomad_v4 ↗
BS2 BS2 requires observation of the variant in a healthy adult individual for a fully penetrant dominant disorder, or observation in trans with a pathogenic variant (in homozygous state) for a recessive disorder. No such observations are available for this variant. No homozygotes are reported in gnomAD. Details ▾Hide ▴
Evidence considered
  • No healthy adult carrier data available
  • No homozygotes in gnomAD v4.1
Still missing
  • No population data on clinical phenotype of carriers
BS3 No well-established in vitro or in vivo functional studies have been identified demonstrating that c.4270-9A>T does not alter splicing or protein function. BS3 requires functional evidence showing no damaging effect. Details ▾Hide ▴
Evidence considered
  • Exploratory evidence search found no functional studies demonstrating no damaging effect
Still missing
  • No benign functional study data available
BS4 No evidence of lack of segregation has been reported. BS4 requires that the variant does not segregate with disease in affected members of a family. No family studies are available for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation data available
Still missing
  • No family co-segregation data
BP2 BP2 requires observation of the variant in trans with a pathogenic variant for a fully penetrant recessive disorder, or in cis with a pathogenic variant in any inheritance pattern. No such observations have been reported for c.4270-9A>T. Details ▾Hide ▴
Evidence considered
  • No observation in trans or cis with a known pathogenic NF1 variant
Still missing
  • No data on phasing with other pathogenic NF1 variants
BP5 BP5 requires that the variant is found in a case with an alternate molecular basis for disease. No such observation has been reported for c.4270-9A>T. Details ▾Hide ▴
Evidence considered
  • No co-occurrence with an alternate pathogenic variant reported
Still missing
  • No case with an alternate genetic cause identified
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is an intronic variant at position -9 of the intron 32 splice acceptor site. It does not fall into the canonical +/-1/2 splice consensus positions, and SpliceAI predicts no splicing impact (max delta = 0.00). The variant does not satisfy the generic ClinGen SVI PVS1 null-variant criteria (nonsense, frameshift, or canonical splice sites per PMC6185798). Details ▾Hide ▴
Evidence considered
  • Intronic substitution at acceptor -9 position
  • SpliceAI max delta score = 0.00 (no predicted splice impact)
  • Variant does not meet generic PVS1 null-variant bucket criteria
Sources
spliceai ↗pvs1_generic_framework ↗
PS1 N/APS1 requires same amino acid change as an established pathogenic variant. This is an intronic variant with no predicted protein consequence (p.?). No same-residue comparator exists. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • no amino acid change predicted
PM5 N/AThis is an intronic variant with no predicted missense amino acid consequence (p.?). No same-residue comparator variants exist for PM5 assessment. The pm5_candidates pipeline confirmed that the variant is ineligible for classic PM5 search. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • no missense residue to compare
PP2 N/APP2 applies to missense variants in genes where missense variants are a common mechanism of disease and benign missense variation is rare. NF1 is a known loss-of-function gene, but this variant is intronic, not missense. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • PP2 is designed for missense variants
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the predominant mechanism of disease. This is an intronic variant (c.4270-9A>T), not a missense variant. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • BP1 is designed for missense variants
BP7 N/ABP7 applies to synonymous variants where splicing prediction algorithms predict no impact on the splice consensus sequence. This variant (c.4270-9A>T) is an intronic substitution, not a synonymous coding variant. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • BP7 is designed for synonymous coding variants
PS5 N/APS5 applies when PM4/PM5 criteria are met but PS1/PS4 cannot be assessed. PM4/PM5 are not met for this intronic variant (no protein-level consequence comparator exists). Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • PM4/PM5 not met
  • so PS5 is not applicable

Identifiers

Gene
NF1
Transcript
NM_000267.3
Coding (HGVS c.)
NM_000267.3:c.4270-9A>T
Protein (HGVS p.)
NP_000258.1:p.?
GRCh38
chr17:31259023 A>T
GRCh37
chr17:29586041 A>T
ClinVar
849602

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 7 / 1,541,860 alleles AF 4.54e-06 · 0 homozygotes · FAF 2.6e-06
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 4.5e-06 · 7 / 1,541,860 alleles · 0 hom · FAF 2.6e-06
European (non-Finnish)7 / 1,121,574 6.2e-06
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 4.53997e-06; MAF= 0.00045%, 7/1541860 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.24123e-06; MAF= 0.00062%, 7/1121574 alleles, homozygotes = 0); grpmax FAF= 2.6e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +49 bp
0.000
SpliceAI acceptor gainat +18 bp
0.000
SpliceAI donor lossat +398 bp
0.000
SpliceAI donor gainat +200 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

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 splicing alteration (max delta score = 0.00, with all four delta scores at 0.00: acceptor gain 0.00, acceptor loss 0.00, donor gain 0.00, donor loss 0.00). The variant is deep intronic and is not predicted to disrupt the native splice site. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.00 (all four delta positions at 0.00)
  • No computational prediction of splicing impact
Sources
spliceai ↗
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splicing impact (max delta = 0.00). REVEL and BayesDel are not available for this intronic variant. No in silico tools predict a damaging consequence. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.00 (acceptor gain 0.00
  • acceptor loss 0.00
  • donor gain 0.00
  • donor loss 0.00)
  • REVEL: not available (intronic)
  • BayesDel: not available (intronic)
Still missing
  • No missense-level in silico scores (REVEL/BayesDel) available for intronic variant
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous variants where splicing prediction algorithms predict no impact on the splice consensus sequence. This variant (c.4270-9A>T) is an intronic substitution, not a synonymous coding variant. Details ▾Hide ▴
Evidence considered
  • Intronic variant
  • BP7 is designed for synonymous coding variants

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

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

  • Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
    Trepanier A et al. · 2004
    No paper-specific finding is recorded.
    PMID 15604628 ↗
  • Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors.
    Radtke HB et al. · 2007
    No paper-specific finding is recorded.
    PMID 17636453 ↗
  • American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.
    Robson ME et al. · 2010
    No paper-specific finding is recorded.
    PMID 20065170 ↗
  • Neurofibromatosis 1.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301288 ↗
  • Wilms Tumor Predisposition.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301471 ↗
  • 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. · 2010
    No paper-specific finding is recorded.
    PMID 20664475 ↗
  • American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.
    Robson ME et al. · 2015
    No paper-specific finding is recorded.
    PMID 26324357 ↗
  • Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis-Practice Resource of the National Society of Genetic Counselors.
    No paper-specific finding is recorded.
    PMID 32602153 ↗
  • Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.
    Lenders JW et al. · 2014
    No paper-specific finding is recorded.
    PMID 24893135 ↗
  • Points to Consider: Ethical, Legal, and Psychosocial Implications of Genetic Testing in Children and Adolescents.
    Botkin JR et al. · 2015
    No paper-specific finding is recorded.
    PMID 26140447 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    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
    No paper-specific finding is recorded.
    PMID 33939658 ↗

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

gnomAD v4.1 7 / 1,541,860 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 1 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= 4.53997e-06; MAF= 0.00045%, 7/1541860 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.24123e-06; MAF= 0.00062%, 7/1121574 alleles, homozygotes = 0); grpmax FAF= 2.6e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

Error retrieving ClinVar entry.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Somatic

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