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LYFE SCIENCES
Project: HERA
NM_000267.3:c.2747A>G
p.Asn916Ser  ·  NF1
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Classification rationale
1

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.

clinvar ↗
2

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.

gnomad_v2 ↗ gnomad_v4 ↗
3

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.

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
  • —
Gaps remaining
  • —
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 v2.1This 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.
gnomAD v4.1This 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.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (2 clinical laboratories).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: 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 ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
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; COSV62223654, n = 1 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueN916
Hotspots ↗