Classification rationale

BP7 VUS

NF1 c.4686A>G

The NF1 c.4686A>G (p.Glu1562=) variant has been reported in ClinVar predominantly as likely benign or benign, with some uncertain significance submissions.¹ This variant is present in population databases, including gnomAD v2.1 at an allele frequency of 0.000226663 (64/282358) and gnomAD v4.1 at an allele frequency of 0.000223144, which is below common benign strong thresholds but inconsistent with absence from controls.² In silico splice prediction does not support a splice-disrupting effect, with SpliceAI showing a maximum delta score of 0.01.³

BP7 → VUS

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 · 1 applied · 17 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 · 1

Strength Supporting Moderate Strong Very strong

BP7 Benign

This variant is a synonymous change, p.(Glu1562=), and available splice prediction does not indicate a significant impact on RNA splicing. SpliceAI shows a maximum delta score of 0.01, which supports BP7.

Protein consequence is p.(Glu1562=).SpliceAI predicts no significant splice impactmax delta score 0.01.

spliceai ↗

Assessed · not applied · 6 not met · 11 not assessed

Pathogenic

PVS1 This variant is a synonymous change, p.(Glu1562=), and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants.

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified.

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

PS4 No case-control enrichment or sufficiently specific case series for this exact variant were identified.

PM1 This variant has not been identified in a mutational hotspot or well-established critical functional domain without benign variation.

PM2 This variant is present in population databases and is not absent or extremely rare.

PM6 No assumed de novo occurrence data for this exact variant were identified.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support a deleterious effect on splicing.

PP4 No phenotype or family-history data specific enough to support PP4 were identified.

Benign

BA1 Population frequency does not meet a stand-alone benign threshold.

BS1 Population frequency is below the usual benign strong threshold.

BS2 Although this variant is present in population databases, no direct evidence was identified showing the variant in a sufficient number of well-phenotyped unaffected individuals for BS2.

BS3 No well-established functional study demonstrating no damaging effect of this specific variant was identified.

BS4 No segregation studies showing lack of segregation with disease were identified.

BP2 No phase data or observations with another pathogenic variant were identified.

BP5 No evidence was identified showing that the observed phenotype is fully explained by an alternate molecular diagnosis.

N/A · 10 PS1 · PM3 · PM4 · PM5 · PP2 · PP5 · BP1 · BP3 · BP4 · BP6

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000223144; MAF= 0.02231%, 360/1613306 alleles, homozygotes = 2) and has highest observed frequency in the Admixed American population (AF= 0.00044979; MAF= 0.04498%, 27/60028 alleles, homozygotes = 1); grpmax FAF= 0.00031689.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000226663; MAF= 0.02267%, 64/282358 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000695217; MAF= 0.06952%, 5/7192 alleles, homozygotes = 0); grpmax FAF= 0.00031301.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.022% · 360 / 1,613,306
2 hom · FAF 0.032%

Admixed American 27 / 60,028	0.045% 1 hom
European (non-Finnish) 302 / 1,179,438	0.026% 1 hom
Remaining individuals 14 / 62,448	0.022%
European (Finnish) 14 / 64,004	0.022%
African/African American 2 / 75,012	0.0027%
South Asian 1 / 91,064	0.0011%

+ 4 not observed (Amish, East Asian, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.023% · 64 / 282,358
0 hom · FAF 0.031%

Remaining individuals 5 / 7,192	0.07%
Admixed American 17 / 35,418	0.048%
European (Finnish) 7 / 25,120	0.028%
European (non-Finnish) 34 / 128,982	0.026%
African/African American 1 / 24,760	0.004%

+ 3 not observed (Ashkenazi Jewish, East Asian, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as 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 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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