Classification rationale

PM2 BP7 VUS

NF1 c.8085A>G

The NF1 c.8085A>G (p.(Gly2695=)) variant has not been observed in somatic cancers in COSMIC and has not been reported in ClinVar.¹ 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%.² 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.³

PM2 + BP7 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000267.3 · variants mapped to exon structure

NF1 NM_000267.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 18 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

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.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP7 supporting Benign

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.

The normalized protein consequence is p.(Gly2695=) / p.(G2695=).SpliceAI predicts no significant splice impact with max delta score 0.01.

spliceai ↗cspec ↗

Assessed · not applied · 3 not met · 15 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with verified parental relationships was identified, so PS2 cannot be assessed from the available evidence.

PS3 No well-established functional studies demonstrating a damaging effect for this specific variant were identified.

PS4 No case-control or prevalence data showing enrichment of this variant in affected individuals were identified.

PM1 Available evidence does not establish that this synonymous variant lies in a mutational hotspot or a critical functional domain without benign variation.

PM3 No phase data or observations in trans with a pathogenic variant were identified.

PM6 No assumed de novo occurrence without full parental confirmation was identified.

PP1 No segregation data were identified for this variant in affected family members.

PP3 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.

PP4 No phenotype or family history information specific enough to support a highly NF1-specific clinical presentation was provided.

PP5 No reputable source classification supporting pathogenicity was identified for this variant.

Benign

BA1 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%.

BS1 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%.

BS2 No evidence was identified showing this variant in healthy adult individuals at a frequency inconsistent with NF1 pathogenicity.

BS3 No well-established functional studies demonstrating a benign effect for this specific variant were identified.

BS4 No family data showing lack of segregation with disease were identified.

BP2 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.

BP5 No alternate molecular diagnosis or other cause explaining the phenotype was identified.

BP6 No reputable source classification supporting a benign interpretation was identified for this variant.

N/A · 8 PVS1 · PS1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP4

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB oncogenicity for this specific variant: Unknown Oncogenic Effect (variant has not been individually curated).

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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