NM_000267.3:c.2747A>G

NF1 · NP_000258.1:p.(Asn916Ser) · NM_000267.3

GRCh37: chr17:29556380 A>G · GRCh38: chr17:31229362 A>G

Gene: NF1 Transcript: NM_000267.3

Final call

VUS

Variant details

Gene

NF1

Transcript

NM_000267.3

Protein

NP_000258.1:p.(Asn916Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The NF1 c.2747A>G (p.Asn916Ser) variant has been reported in ClinVar with conflicting germline classifications, including uncertain significance and likely benign, and without an expert panel assertion.

This variant is present at low frequency in population databases: gnomAD v4.1 shows an allele frequency of 0.00570% (92/1613808 alleles; grpmax FAF 0.006229%) and gnomAD v2.1 shows an allele frequency of 0.00239% (6/251122 alleles), which is below benign frequency thresholds but means the variant is not absent from controls.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, so in silico splicing evidence does not independently support pathogenicity.

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 available PVS1 assessment indicates it does not fall within the null-variant categories used for generic PVS1 application.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence was identified that this amino acid change has been established as the same pathogenic amino acid substitution caused by a different nucleotide change.	clinvar
PS2	Not assessed	No confirmed de novo data with parental testing were identified.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect of this specific variant were identified.	oncokb
PS4	Not met	Available evidence does not show enrichment of this variant in affected individuals over controls, and no case-control or multiple independent affected-case data were identified.	clinvar
PM1	Not met	This variant has not been shown to lie in an established mutational hotspot or a well-characterized critical functional domain without benign variation.	hotspots
PM2	Not met	This variant is present in population databases and therefore is not absent from controls. In gnomAD v4.1 the overall allele frequency is 0.00570% (92/1613808) with grpmax FAF 0.006229%, and in gnomAD v2.1 the overall allele frequency is 0.00239% (6/251122).	gnomad_v2 gnomad_v4
PM4	N/A	This variant is a missense substitution and does not produce a protein length change.
PM5	Not met	Other missense substitutions at codon 916 were identified, but no pathogenic or likely pathogenic missense change at this residue was established to support PM5.	clinvar
PM6	Not assessed	No assumed de novo occurrence without confirmed parental testing was identified.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	Not assessed	Available evidence does not establish that missense variation in NF1 is sufficiently constrained in a way that supports applying PP2 to this variant.	cspec
PP3	Not met	Available computational evidence does not reach a level that independently supports a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01.	spliceai
PP4	Not assessed	No phenotype or family-history data were provided that would be sufficiently specific to NF1 for PP4 assessment.
PP5	N/A	PP5 was not applied because external assertions without independently reviewable evidence are not used as standalone support.	clinvar
BA1	Not met	Population frequency is well below a benign stand-alone threshold. In gnomAD v4.1 the overall allele frequency is 0.00570% and the highest population frequency is 0.00754%, both far below 1%.	gnomad_v4
BS1	Not met	Population frequency is below a benign strong threshold. In gnomAD v4.1 the overall allele frequency is 0.00570% and the highest population frequency is 0.00754%, both below 0.3%.	gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in well-phenotyped unaffected individuals at an age appropriate for the disorder.
BS3	Not assessed	No well-established functional studies demonstrating a benign effect of this specific variant were identified.	oncokb
BS4	Not assessed	No family data were identified showing lack of segregation with disease.
BP1	Not assessed	Available evidence does not support applying BP1 to this NF1 missense variant.	cspec
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic variant or in cis with another pathogenic variant.
BP3	N/A	BP3 is intended for in-frame insertions or deletions in repetitive regions and is not applicable to this missense substitution.
BP4	Not met	Available computational evidence does not provide independent support for a benign effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but this alone is insufficient to establish BP4 for a missense change.	spliceai
BP5	Not assessed	No alternate molecular explanation for the phenotype was identified.
BP6	N/A	BP6 was not applied because external assertions without independently reviewable evidence are not used as standalone support.	clinvar
BP7	N/A	BP7 is not applicable because this variant is not synonymous or intronic.

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.