Variant classification summary

NM_000267.3:c.8085A>G

NF1 · NP_000258.1:p.(Gly2695=) · NM_000267.3

GRCh37: chr17:29686021 A>G · GRCh38: chr17:31359003 A>G

Gene: NF1 Transcript: NM_000267.3

Final call

VUS

PM2_Supporting BP7_Supporting

Variant details

Gene

NF1

Transcript

NM_000267.3

Protein

NP_000258.1:p.(Gly2695=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The NF1 c.8085A>G (p.(Gly2695=)) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, with an observed population frequency of 0 in both datasets, which is below the PM2 rarity threshold of 0.1%.

3

This is a synonymous change, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which supports BP7 and argues against a predicted RNA effect.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	NF1 loss of function is an established disease mechanism, but this variant is a synonymous substitution and is not a nonsense, frameshift, or canonical ±1,2 splice-site change, so PVS1 does not apply.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 is intended for a variant that results in the same amino acid change as an established pathogenic variant; this variant is synonymous and no alternate pathogenic amino acid substitution was identified.	cspec
PS2	Not assessed	No confirmed de novo occurrence with verified parental relationships was identified, so PS2 cannot be assessed from the available evidence.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect for this specific variant were identified.
PS4	Not assessed	No case-control or prevalence data showing enrichment of this variant in affected individuals were identified.	clinvar
PM1	Not assessed	Available evidence does not establish that this synonymous variant lies in a mutational hotspot or a critical functional domain without benign variation.	hotspots
PM2	Met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 (observed frequency 0 in both datasets), which is below the PM2 rarity threshold of 0.1% and supports rarity in the general population.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No phase data or observations in trans with a pathogenic variant were identified.
PM4	N/A	PM4 applies to protein length changes from in-frame insertions, deletions, or stop-loss variants; this variant is a synonymous substitution and does not alter protein length.	cspec
PM5	N/A	PM5 is intended for a novel missense change at an amino acid residue where a different pathogenic missense change has been established; this variant is synonymous.	cspec
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified.
PP1	Not assessed	No segregation data were identified for this variant in affected family members.
PP2	N/A	PP2 is used for missense variants in genes with a low rate of benign missense variation and a common pathogenic missense mechanism; this variant is not missense.	cspec
PP3	Not met	Computational evidence does not support a deleterious effect because this synonymous variant has a SpliceAI maximum delta score of 0.01, which predicts no significant splice impact.	spliceai
PP4	Not assessed	No phenotype or family history information specific enough to support a highly NF1-specific clinical presentation was provided.
PP5	Not assessed	No reputable source classification supporting pathogenicity was identified for this variant.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 (observed frequency 0 in both datasets), which is below the BA1 benign threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1 and gnomAD v4.1 (observed frequency 0 in both datasets), which is below the BS1 benign threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals at a frequency inconsistent with NF1 pathogenicity.
BS3	Not assessed	No well-established functional studies demonstrating a benign effect for this specific variant were identified.
BS4	Not assessed	No family data showing lack of segregation with disease were identified.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism; this variant is synonymous and not missense.	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 a pathogenic variant.
BP3	N/A	BP3 applies to in-frame insertions or deletions in repetitive regions without known function; this variant is a synonymous single-nucleotide substitution.	cspec
BP4	N/A	For this synonymous variant, benign computational evidence is more appropriately captured by BP7 rather than BP4.	spliceai cspec
BP5	Not assessed	No alternate molecular diagnosis or other cause explaining the phenotype was identified.
BP6	Not assessed	No reputable source classification supporting a benign interpretation was identified for this variant.	clinvar
BP7	Met	This is a synonymous NF1 variant, p.(Gly2695=), and SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, supporting that the change is unlikely to alter the protein or RNA product.	spliceai cspec

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