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LYFE SCIENCES
Project: HERA
NM_002524.4:c.31G>A
p.Ala11Thr  ·  NRAS
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Classification rationale
1

The NRAS c.31G>A (p.Ala11Thr) variant has been reported in ClinVar with an expert panel interpretation of uncertain significance and has also been curated in variant-specific cancer resources.

clinvar ↗ oncokb ↗
2

This variant is present at very low frequency in population databases, with 1/251492 alleles in gnomAD v2.1 (AF 0.00040%) and 1/1613858 alleles in gnomAD v4.1 (AF 0.000062%).

gnomad_v2 ↗ gnomad_v4 ↗
3

The p.Ala11Thr change lies within the NRAS P-loop (amino acids 10-17), a RASopathy VCEP-specified critical functional domain, which supports PM1.

cspec ↗
4

SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.00), the REVEL score is 0.412, and the BayesDel score is 0.00411725; these values do not meet the RASopathy VCEP thresholds for either PP3 or BP4.

cspec ↗ 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
—
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= 3.97627e-06; MAF= 0.00040%, 1/251492 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 6.19633e-07; MAF= 0.00006%, 1/1613858 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66594e-05; MAF= 0.00167%, 1/60026 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.412. BayesDel score = 0.00411725.
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; COSV54738286, n = 3 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueA11
Hotspots ↗