Classification rationale

BP4 VUS

NF1 c.2033C>T

The NF1 c.2033C>T (p.Pro678Leu) variant has been reported in ClinVar, where most submissions classify it as likely benign or benign, with one submission classifying it as uncertain significance.¹ This variant is absent from gnomAD v2.1 but is present in gnomAD v4.1 at 229/1613768 alleles overall (AF 0.01419%), with the highest observed frequency in the African/African American population at 139/75006 alleles (AF 0.18532%) and one homozygote reported.² Available computational evidence supports no meaningful functional impact, with SpliceAI showing no predicted splice effect (maximum delta score 0.00), REVEL at 0.141, and BayesDel at -0.334865.³

BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗revelbayesdel

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 · 19 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

BP4 supporting review Benign

Multiple computational predictors support a benign effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, REVEL is 0.141, and BayesDel is -0.334865, which together argue against a damaging effect.

SpliceAI max delta score 0.00.REVEL score 0.141.BayesDel score -0.334865.

spliceai ↗

Assessed · not applied · 8 not met · 11 not assessed

Pathogenic

PS1 No evidence was identified showing that a different nucleotide change produces the same amino acid substitution with an established pathogenic classification.

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

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

PS4 This variant has been reported in ClinVar, but the available evidence does not show enrichment in affected individuals over controls, and the variant is also present in gnomAD.

PM1 Available evidence does not show that codon 678 lies in a mutational hotspot or in a well-established critical region without benign variation, and Cancer Hotspots did not identify a statistically significant hotspot at this residue.

PM2 This variant is present in gnomAD v4.1, with a highest observed population frequency of 0.18532% in the African/African American population, which is above the <0.1% rarity threshold used for PM2.

PM5 No evidence was identified that a different missense change at codon 678 has been established as pathogenic.

PM6 No probable de novo occurrence without full parental confirmation was identified for this variant.

PP1 No segregation data were identified for this variant.

PP2 Available evidence does not establish a gene-specific missense-only mechanism or a sufficiently low rate of benign missense variation to support PP2 for this variant.

PP3 Available computational evidence does not support a deleterious effect.

PP4 No individual-level phenotype data were identified that would support a highly specific clinical presentation for this variant.

Benign

BA1 This variant does not meet the stand-alone benign frequency threshold because the highest observed population frequency in gnomAD v4.1 is 0.18532%, which is below the >1% BA1 threshold.

BS1 This variant does not meet the strong benign frequency threshold because the highest observed population frequency in gnomAD v4.1 is 0.18532%, which is below the >0.3% BS1 threshold.

BS2 This variant is present in gnomAD v4.1 with one homozygote, but no phenotype information is available for population database participants, so this observation alone does not establish BS2.

BS3 No well-established functional study demonstrating normal function of this exact variant was identified.

BS4 No nonsegregation data were identified for this variant.

BP2 No phase information with another pathogenic variant was identified.

BP5 No alternate molecular explanation for the observed phenotype was identified from the available evidence.

N/A · 8 PVS1 · PM3 · PM4 · PP5 · BP1 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000141904; MAF= 0.01419%, 229/1613768 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00185319; MAF= 0.18532%, 139/75006 alleles, homozygotes = 0); grpmax FAF= 0.00160212.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.014% · 229 / 1,613,768
1 hom · FAF 0.16%

African/African American 139 / 75,006	0.19%
East Asian 32 / 44,880	0.071%
Remaining individuals 16 / 62,480	0.026%
South Asian 21 / 91,064	0.023% 1 hom
Admixed American 9 / 59,964	0.015%
European (non-Finnish) 12 / 1,179,796	0.001%

+ 4 not observed (European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (4 clinical laboratories) and as Uncertain significance (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.141. BayesDel score = -0.334865.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. 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; COSV62204740, n = 3 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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