Variant classification summary

NM_000267.3:c.702_704delinsATT

NF1 · NP_000258.1:p.(Tyr235Phe) · NM_000267.3

GRCh37: chr17:29508775 GTA>ATT · GRCh38: chr17:31181757 GTA>ATT

Gene: NF1 Transcript: NM_000267.3

Final call

VUS

PM2 supporting

Variant details

Gene

NF1

Transcript

NM_000267.3

Protein

NP_000258.1:p.(Tyr235Phe)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The NF1 c.702_704delinsATT (p.Tyr235Phe) 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

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, but no REVEL or BayesDel score was available to support or refute a deleterious missense effect.

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 variant results in p.(Tyr235Phe), an amino-acid substitution, and does not fall into the default PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1 or 2 splice-site variants. SpliceAI also predicts no significant splice impact (max delta score 0.01), so available evidence does not support applying PVS1.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework spliceai
PS1	Not assessed	No pathogenic or likely pathogenic variant causing the same amino-acid change, p.(Tyr235Phe), was identified in the reviewed evidence, so PS1 was not established.	clinvar cspec
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified for this variant, so PS2 could not be applied.	clinvar
PS3	Not assessed	No well-established functional study demonstrating a damaging effect of this exact variant was identified, so PS3 was not applied.	oncokb
PS4	Not assessed	No enrichment data, odds ratio, or multiple independent affected observations sufficient for PS4 were identified for this variant.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	This variant has not been shown to lie in a well-established functional domain or statistically significant hotspot without benign variation. Cancer Hotspots did not identify a significant hotspot at residue Y235, so PM1 is not supported by the reviewed evidence.	hotspots cspec
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets and meeting PM2 at supporting strength.	gnomad_v2 gnomad_v4 cspec
PM3	N/A	PM3 is intended for recessive disorders with evidence of the variant in trans with a pathogenic variant. NF1 is evaluated here in an autosomal dominant disease context, so PM3 is not applicable.	cspec
PM4	N/A	Although described as a delins at the coding level, this variant results in a single amino-acid substitution, p.(Tyr235Phe), without a protein length change, so PM4 is not applicable.	pvs1_variant_assessment
PM5	N/A	Available evidence did not identify any accepted same-residue pathogenic comparator, and the reviewed materials could not confirm that classic same-residue PM5 logic should be applied for this case. PM5 was therefore not used.	pm5_candidates cspec
PM6	Not assessed	No assumed de novo occurrence without full parentage confirmation was identified for this variant, so PM6 could not be applied.	clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 could not be applied.	clinvar
PP2	Not assessed	Available evidence did not establish a gene-specific basis to apply PP2 for this missense variant, so PP2 was not assessed.	cspec
PP3	Not assessed	SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), but no REVEL or BayesDel score was available to assess the missense effect itself. Available computational evidence is therefore insufficient to support PP3.	spliceai
PP4	Not assessed	No phenotype information was provided that was sufficiently specific to NF1 to support PP4 for this variant.	cspec
PP5	N/A	PP5 was not used. No ClinVar assertion was identified for this variant, and assertion-only criteria are not used as stand-alone evidence here.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and is therefore well below any benign stand-alone population threshold. BA1 is not met.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and v4.1 and is therefore below benign strong population frequency thresholds. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not assessed	No observation of this variant in healthy adults with adequate penetrance context was identified, so BS2 could not be applied.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study showing normal NF1 function for this exact variant was identified, so BS3 was not applied.	oncokb
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 could not be applied.	clinvar
BP1	Not met	Available evidence does not support BP1. This variant is a missense change, and missense variation is a recognized variant class in NF1 interpretation rather than a class that is uniformly non-contributory.	cspec
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with another pathogenic variant, so BP2 could not be applied.	clinvar
BP3	N/A	BP3 applies to certain in-frame insertions or deletions in repetitive regions without known function. This variant produces a single amino-acid substitution rather than an in-frame length change, so BP3 is not applicable.	pvs1_variant_assessment
BP4	Not met	SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), but no REVEL or BayesDel score was available to support a benign missense interpretation. Available computational evidence is insufficient to meet BP4.	spliceai
BP5	Not assessed	No alternative molecular diagnosis or alternate cause for disease was identified from the reviewed evidence, so BP5 could not be applied.	cspec
BP6	N/A	BP6 was not used. No ClinVar benign or likely benign assertion was identified for this variant, and assertion-only criteria are not used as stand-alone evidence here.	clinvar
BP7	N/A	BP7 applies to synonymous or certain noncoding variants without predicted splice impact. This variant is a missense change, so BP7 is not applicable.	spliceai

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