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LYFE SCIENCES
Project: HERA
NM_000267.3:c.2033C>T
p.Pro678Leu  ·  NF1
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
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 ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
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 ↗
COSMIC evidence
05
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).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueP678
Hotspots ↗