NM_000267.3:c.2033C>T

NF1 · NP_000258.1:p.(Pro678Leu) · NM_000267.3

GRCh37: chr17:29553484 C>T · GRCh38: chr17:31226466 C>T

Gene: NF1 Transcript: NM_000267.3

Final call

VUS

BP4 supporting

Variant details

Gene

NF1

Transcript

NM_000267.3

Protein

NP_000258.1:p.(Pro678Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The NF1 c.2033C>T (p.Pro678Leu) variant has been reported in ClinVar, where most submissions classify it as likely benign or benign, with one submission classifying it as uncertain significance.

This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 229/1613768 alleles overall (AF 0.01419%), with the highest observed frequency in the African/African American population at 139/75006 alleles (AF 0.18532%) and one homozygote reported.

Available computational evidence supports no meaningful functional impact, with SpliceAI showing no predicted splice effect (maximum delta score 0.00), REVEL at 0.141, and BayesDel at -0.334865.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant, and the available PVS1 assessments indicate that it does not fall within the default null-variant categories for PVS1 application.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence was identified showing that a different nucleotide change produces the same amino acid substitution with an established pathogenic classification.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.	clinvar PMID:23460398
PS3	Not assessed	No well-established functional study demonstrating a damaging effect of this exact variant was identified.	oncokb
PS4	Not met	This variant has been reported in ClinVar, but the available evidence does not show enrichment in affected individuals over controls, and the variant is also present in gnomAD.	clinvar gnomad_v4
PM1	Not met	Available evidence does not show that codon 678 lies in a mutational hotspot or in a well-established critical region without benign variation, and Cancer Hotspots did not identify a statistically significant hotspot at this residue.	hotspots
PM2	Not met	This variant is present in gnomAD v4.1, with a highest observed population frequency of 0.18532% in the African/African American population, which is above the <0.1% rarity threshold used for PM2.	gnomad_v2 gnomad_v4
PM3	N/A	No recessive-phase evidence was identified, and PM3 is not applicable to this case based on the available evidence.
PM4	N/A	This is a missense substitution and does not produce a protein length change from an in-frame insertion/deletion or stop-loss event.
PM5	Not met	No evidence was identified that a different missense change at codon 678 has been established as pathogenic.	clinvar
PM6	Not assessed	No probable de novo occurrence without full parental confirmation was identified for this variant.	clinvar PMID:23460398
PP1	Not assessed	No segregation data were identified for this variant.	clinvar
PP2	Not assessed	Available evidence does not establish a gene-specific missense-only mechanism or a sufficiently low rate of benign missense variation to support PP2 for this variant.	cspec
PP3	Not met	Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.141, and BayesDel is -0.334865.	spliceai revel bayesdel
PP4	Not assessed	No individual-level phenotype data were identified that would support a highly specific clinical presentation for this variant.	clinvar
PP5	N/A	External classification assertions were identified in ClinVar, but reputable-source assertions alone were not used as stand-alone evidence for this criterion.	clinvar
BA1	Not met	This variant does not meet the stand-alone benign frequency threshold because the highest observed population frequency in gnomAD v4.1 is 0.18532%, which is below the >1% BA1 threshold.	gnomad_v4
BS1	Not met	This variant does not meet the strong benign frequency threshold because the highest observed population frequency in gnomAD v4.1 is 0.18532%, which is below the >0.3% BS1 threshold.	gnomad_v4
BS2	Not assessed	This variant is present in gnomAD v4.1 with one homozygote, but no phenotype information is available for population database participants, so this observation alone does not establish BS2.	gnomad_v4
BS3	Not assessed	No well-established functional study demonstrating normal function of this exact variant was identified.	oncokb
BS4	Not assessed	No nonsegregation data were identified for this variant.	clinvar
BP1	N/A	BP1 is not applicable because missense variation is a recognized disease mechanism in NF1 and this is not a gene where primarily truncating variants alone account for disease.	cspec
BP2	Not assessed	No phase information with another pathogenic variant was identified.	clinvar
BP3	N/A	This is not an in-frame deletion or insertion in a repetitive region without known function.
BP4	Met	Multiple computational predictors support a benign effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.141, and BayesDel is -0.334865, which together argue against a damaging effect.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular explanation for the observed phenotype was identified from the available evidence.
BP6	N/A	Benign and likely benign assertions are present in ClinVar, but external assertions alone were not used as stand-alone benign evidence for this criterion.	clinvar
BP7	N/A	This is a missense variant and not a synonymous or deep intronic change for which BP7 would be considered.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.