Variant classification summary

NM_000267.3:c.8089_8093delinsGTTTT

NF1 · NP_000258.1:p.(Phe2697_Ser2698delinsValLeu) · NM_000267.3

GRCh37: chr17:29686025 TTTTC>GTTTT · GRCh38: chr17:31359007 TTTTC>GTTTT

Gene: NF1 Transcript: NM_000267.3

Final call

VUS

PM2 supporting

Variant details

Gene

NF1

Transcript

NM_000267.3

Protein

NP_000258.1:p.(Phe2697_Ser2698delinsValLeu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The NF1 c.8089_8093delinsGTTTT (p.(Phe2697_Ser2698delinsValLeu)) variant has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.

3

No variant-specific reviewed functional study was identified for this exact NF1 change.

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01; no REVEL or BayesDel result was available in the reviewed files for this protein-altering delins.

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	Not met	NF1 loss of function is an established disease mechanism, but this variant is an in-frame protein-altering delins rather than a nonsense, frameshift, or canonical splice-site variant, and SpliceAI predicts no significant splice impact (max delta score 0.01). Available evidence therefore does not support application of PVS1.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework spliceai
PS1	Not assessed	No evidence was identified showing that this variant produces the same amino acid change as a previously established pathogenic variant.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified for this variant.	clinvar
PS3	Not assessed	No well-established functional study for this exact variant was identified, so functional evidence supporting a damaging effect is not available.	oncokb
PS4	Not assessed	No enrichment data, case-control evidence, or count of multiple unrelated affected individuals with this exact variant was identified.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	Available evidence does not show that this variant lies in an established NF1 mutational hotspot or a critical functional domain without benign variation. Cancer Hotspots did not identify a statistically significant hotspot at this site, although the hotspot review was flagged for human review.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the PM2 threshold of 0.1% for rarity-based support.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable because this criterion is used for recessive disorders and no recessive phase-based evidence is relevant here.	cspec
PM4	Not met	This variant results in an in-frame amino acid substitution-delins, p.(Phe2697_Ser2698delinsValLeu), without a net protein length change, so available evidence does not support PM4.	spliceai
PM5	N/A	PM5 is not applicable because no evidence was identified for a different established pathogenic missense change at the same amino acid residue, and this variant is a two-residue in-frame delins rather than a single-residue missense substitution.	clinvar
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so cosegregation with disease cannot be assessed.	clinvar
PP2	N/A	PP2 is intended for missense variants in genes with a low rate of benign missense variation, and this variant is a two-residue in-frame delins rather than a missense substitution.	cspec
PP3	Not met	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01. No additional validated computational predictor result was available to support a damaging effect for this protein-altering delins, so PP3 is not supported.	spliceai
PP4	Not assessed	No phenotype information was provided that would allow assessment of whether the observed clinical presentation is highly specific for an NF1-related disorder caused by this gene.	cspec
PP5	Not assessed	No reputable source classification for this exact variant was identified in the reviewed materials.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the BA1 threshold of 1% and does not support a benign stand-alone classification.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, corresponding to an observed population frequency of 0%, which is below the BS1 threshold of 0.3% and does not support a benign frequency-based interpretation.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adults for whom penetrance expectations would argue against pathogenicity.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing a normal or benign effect for this exact variant was identified.	oncokb
BS4	Not assessed	No family data were identified showing lack of segregation of this variant with disease.	clinvar
BP1	N/A	BP1 is a missense-specific criterion and is not applicable to this two-residue in-frame delins.	cspec
BP2	Not assessed	No phase information or second variant data were identified to assess whether this variant occurs in trans with a pathogenic variant or in cis with another variant.	clinvar
BP3	Not assessed	No evidence was identified showing that this in-frame change lies within a repetitive region without known function.	cspec
BP4	Not met	SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, but this alone does not establish a benign overall effect for a protein-altering delins. No additional validated benign computational predictor result was available, so BP4 is not supported.	spliceai
BP5	Not assessed	No evidence was identified for an alternate molecular explanation that would make this variant an incidental finding unrelated to the phenotype.	cspec
BP6	Not assessed	No reputable benign classification for this exact variant was identified in the reviewed materials.	clinvar
BP7	N/A	BP7 is not applicable because this variant is a coding in-frame delins rather than a synonymous or intronic variant.	spliceai

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