Classification rationale

VUS

NF1 c.2747A>G

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.¹ 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.² 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.³

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

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 · 0 applied · 21 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 · 0

No criteria were applied for this variant.

Assessed · not applied · 9 not met · 12 not assessed

Pathogenic

PS1 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.

PS2 No confirmed de novo data with parental testing were identified.

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

PS4 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.

PM1 This variant has not been shown to lie in an established mutational hotspot or a well-characterized critical functional domain without benign variation.

PM2 This variant is present in population databases and therefore is not absent from controls.

PM5 Other missense substitutions at codon 916 were identified, but no pathogenic or likely pathogenic missense change at this residue was established to support PM5.

PM6 No assumed de novo occurrence without confirmed parental testing was identified.

PP1 No segregation data were identified for this variant.

PP2 Available evidence does not establish that missense variation in NF1 is sufficiently constrained in a way that supports applying PP2 to this variant.

PP3 Available computational evidence does not reach a level that independently supports a deleterious effect.

PP4 No phenotype or family-history data were provided that would be sufficiently specific to NF1 for PP4 assessment.

Benign

BA1 Population frequency is well below a benign stand-alone threshold.

BS1 Population frequency is below a benign strong threshold.

BS2 No evidence was identified showing this variant in well-phenotyped unaffected individuals at an age appropriate for the disorder.

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

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

BP1 Available evidence does not support applying BP1 to this NF1 missense variant.

BP2 No phase data were identified showing this variant in trans with a pathogenic variant or in cis with another pathogenic variant.

BP4 Available computational evidence does not provide independent support for a benign effect.

BP5 No alternate molecular explanation for the phenotype was identified.

N/A · 6 PVS1 · PM4 · PP5 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 5.7008e-05; MAF= 0.00570%, 92/1613808 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.54351e-05; MAF= 0.00754%, 89/1179822 alleles, homozygotes = 0); grpmax FAF= 6.229e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 2.38928e-05; MAF= 0.00239%, 6/251122 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.2897e-05; MAF= 0.00529%, 6/113428 alleles, homozygotes = 0); grpmax FAF= 2.298e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0057% · 92 / 1,613,808
0 hom · FAF 0.0062%

European (non-Finnish) 89 / 1,179,822	0.0075%
Remaining individuals 2 / 62,470	0.0032%
African/African American 1 / 74,918	0.0013%

+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0024% · 6 / 251,122
0 hom · FAF 0.0023%

European (non-Finnish)

6 / 113,428

0.0053%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (2 clinical laboratories).

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: NF1, a negative regulator of RAS, is inactivated by mutation or deletion in various solid and hematologic malignancies.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV62223654, n = 1 times).

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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