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.1 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%).2 The p.Ala11Thr change lies within the NRAS P-loop (amino acids 10-17), a RASopathy VCEP-specified critical functional domain, which supports PM1.3 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 BP4.4
NRAS
Final classification
VUS
NRAS c.31G>A · p.Ala11Thr
NRAS
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.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PM1 moderate; no rule matched the adjudicated criteria.
Classification rationale
PM1
VUS
NRAS c.31G>A
PM1
→
VUS
3
cspec ↗vcep_alignment_with_pm1_domains_pptx
4
cspec ↗spliceai ↗revelbayesdel
Gene diagram
· NM_002524.4 · variants mapped to exon structure
NRAS
NM_002524.4
Fetching transcript structure from UCSC…
Applied criteria · 1 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This 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).
v2.1
This 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).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
6.2e-05%
· 1 / 1,613,858
0 hom
0 hom
Admixed American 1 / 60,026 |
0.0017% |
+ 9 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
gnomAD v2.1
0.0004%
· 1 / 251,492
0 hom
0 hom
Admixed American 1 / 34,592 |
0.0029% |
+ 7 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
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).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.412. BayesDel score = 0.00411725.
Functional
Likely Neutral
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
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; COSV54738286, n = 3 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links