Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000267.1 | Alternative | 8959 nt | 212–8668 |
| NM_000267.3 | Alternative | 12381 nt | 384–8840 |
| NM_000267.2 | Alternative | 12331 nt | 334–8790 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
Open"This variant has been reported in ClinVar as Benign (2 clinical laboratories) and as Likely benign (7 clinical laboratories) and as Uncertain significance (3 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | -24 bp |
| Donor Loss (DL) | 0.0 | 86 bp |
| Acceptor Gain (AG) | 0.0 | -17 bp |
| Donor Gain (DG) | 0.0 | 17 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to standard ACMG guidelines, the rule for PVS1 is: "Null Variant (nonsense, fs, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease". The evidence for this variant shows it is a synonymous (silent) change not predicted to affect splicing. Therefore, this criterion is not applied because the variant does not introduce a null effect.
PS1 (Not Applied)
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change". The evidence for this variant shows no amino acid change (synonymous). Therefore, this criterion is not applied because there is no amino acid alteration matching a known pathogenic variant.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". There is no data on de novo occurrence for this variant. Therefore, this criterion is not applied due to absence of de novo evidence.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows no functional studies have been performed. Therefore, this criterion is not applied because required functional data are missing.
PS4 (Not Applied)
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls". No case-control or case series data are available for this variant. Therefore, this criterion is not applied due to lack of prevalence data in affected individuals.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hotspot and/or critical and well-established functional domain". The evidence shows this is a synonymous variant outside known critical domains. Therefore, this criterion is not applied because the variant is not located in a known hotspot or critical domain.
PM2 (Moderate)
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium". The evidence for this variant shows a MAF of 0.0227% in gnomAD, representing an extremely low frequency in controls. Therefore, this criterion is applied at Moderate strength because the variant is extremely rare in population databases.
PM3 (Not Applied)
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant". NF1 is a dominant disorder and no trans observations with a pathogenic variant are reported. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants". This variant is synonymous and does not alter protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before". This variant is not a missense change. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity". There is no de novo evidence for this variant. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to standard ACMG guidelines, the rule for PP1 is: "Cosegregation with disease in multiple affected family members". No segregation data are available for this variant. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease". This variant is synonymous, not missense. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product". Computational tools including SpliceAI predict no impact on splicing and no deleterious impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient's phenotype or family history is highly specific for gene". No specific phenotype or family history data are provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic". ClinVar submissions include benign and likely benign calls, but no reputable source has reported this as pathogenic. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium". The variant MAF is 0.0227%, well below 5%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for disorder". The variant MAF of 0.0227% does not exceed expected frequency thresholds for NF1. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder". No such observations are reported. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Well-established in vitro or in vivo functional studies show no damaging effect". No functional studies exist. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family". Segregation analysis data are not available. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene for which primarily truncating variants are known to cause disease". This variant is synonymous, not missense. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant (for dominant disorders)". No trans data are reported. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function". This variant is synonymous, not an indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product". In silico tools including SpliceAI predict no splicing impact and no deleterious effect. Therefore, this criterion is applied at Supporting strength because computational evidence indicates no functional impact.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". No cases with alternative molecular diagnoses are reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign". Although ClinVar includes benign and likely benign calls, the underlying evidence is not accessible for independent review. Therefore, this criterion is not applied.
BP7 (Supporting)
According to standard ACMG guidelines, the rule for BP7 is: "A synonymous variant for which splicing prediction algorithms predict no impact on splicing and the nucleotide is not highly conserved". SpliceAI score is 0.01 indicating no splicing impact and the variant is synonymous. Therefore, this criterion is applied at Supporting strength.