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
Final classification
VUS
PM1
NRAS
c.31G>A
p.Ala11Thr
This variant
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
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_002524.4 · variants mapped to exon structure
NRAS
NM_002524.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 17 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
PM1
moderate
Pathogenic
This missense variant affects NRAS residue Ala11, which lies within the P-loop region (amino acids 10-17), a RASopathy VCEP-specified critical and well-established functional domain; this supports PM1 at Moderate strength.
Protein consequence p.(Ala11Thr)RASopathy VCEP PM1 domain list includes the P-loop at amino acids 10-17
Assessed · not applied
· 9 not met · 8 not assessed
Pathogenic
PS1
Available evidence does not identify a previously established pathogenic variant with the same amino acid change that would support PS1.
PS2
No confirmed de novo occurrence with documented maternity and paternity confirmation was identified for this variant.
PS3
Published functional literature was identified, but the available materials do not provide a reviewed result from one or more RASopathy VCEP-approved assays for this exact variant that is sufficient to apply PS3.
PS4
This variant has been reported in ClinVar, but no secure count of unrelated affected individuals with this exact variant or case-control enrichment data was identified to support PS4 scoring.
PM2
This variant is not absent from population databases.
PM4
This variant is a missense substitution and does not cause a protein length change, so PM4 is not met.
PM5
Available evidence does not identify a different pathogenic or likely pathogenic amino acid change at NRAS codon 11 that would support PM5.
PM6
No presumed de novo occurrence without full parentage confirmation was identified for this variant.
PP1
No segregation data were identified for this variant, so PP1 cannot be applied.
PP3
For missense variants, the RASopathy VCEP applies PP3 when REVEL is at least 0.7.
Benign
BA1
The RASopathy VCEP BA1 threshold is a filtering allele frequency of at least 0.05%.
BS1
The RASopathy VCEP BS1 threshold is a filtering allele frequency of at least 0.025%.
BS2
No evidence was identified showing this variant in a sufficient number of apparently unaffected individuals to support BS2.
BS4
No non-segregation data were identified for this variant, so BS4 cannot be applied.
BP2
No evidence was identified that this variant occurred with an alternative molecular explanation in cis or trans that would support BP2 scoring.
BP4
For missense variants, the RASopathy VCEP applies BP4 when REVEL is 0.3 or lower.
BP5
No evidence was identified for an alternative molecular cause that would explain the phenotype and support BP5 scoring.
N/A · 10
PVS1 · PM3 · PP2 · PP4 · PP5 · BS3 · 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= 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