Classification rationale

BA1BS1BP6BP7 Benign

NRAS c.159G>A

The NRAS c.159G>A (p.Leu53=) variant has not been observed in somatic cancers in COSMIC and is reported in ClinVar as Benign by the ClinGen RASopathy Variant Curation Expert Panel.¹ This variant is present in gnomAD, with the highest observed East Asian allele frequency of 0.12545% in v2.1 and 0.06181% in v4.1, which are above the NRAS RASopathy BA1 threshold of 0.05% and BS1 threshold of 0.025%.² SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.04, supporting no expected RNA effect.³

BA1 + BS1 + BP6 + BP7 → Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

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 · 4 applied · 12 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 · 4

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

Population frequency exceeds the NRAS RASopathy BA1 threshold. In gnomAD v2.1, the highest observed population frequency is 0.12545% in East Asian individuals, which is above the BA1 threshold of 0.05%; gnomAD v4.1 also shows an East Asian frequency of 0.06181%, which is above this threshold.

gnomAD v2.1 East Asian AF 0.0012545162585307105 (0.12545%)25/19928 alleles.gnomAD v4.1 East Asian AF 0.0006181106418048831 (0.06181%)

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BS1 strong Benign

Population frequency exceeds the NRAS RASopathy BS1 threshold. In gnomAD v2.1, the highest observed population frequency is 0.12545% in East Asian individuals, which is above the BS1 threshold of 0.025%; gnomAD v4.1 also shows an East Asian frequency of 0.06181%, which is above this threshold.

gnomAD v2.1 East Asian AF 0.0012545162585307105 (0.12545%).gnomAD v4.1 East Asian AF 0.0006181106418048831 (0.06181%).BS1 threshold in NRAS RASopathy specification is filtering allele frequency ≥0.025%.

gnomad_v2 ↗gnomad_v4 ↗cspec ↗

BP6 supporting Benign

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.

NRAS VCEP lists BP6 as not applicable.ClinVar expert panel classification

cspec ↗clinvar ↗

BP7 supporting Benign

This is a synonymous variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, supporting BP7.

Variant consequence is NP_002515.1:p.(Leu53=).SpliceAI max delta score is 0.04below a level suggesting meaningful splice disruption.

spliceai ↗cspec ↗

Assessed · not applied · 3 not met · 9 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with sufficient parental confirmation and phenotype detail was identified for this variant, so PS2 cannot be assigned from the available evidence.

PS3 No variant-specific approved functional study was identified for this synonymous variant, so PS3 cannot be applied.

PS4 No affected-proband count or case enrichment data were identified for this exact variant, so PS4 cannot be scored.

PM1 This variant is at codon 53, which is outside the NRAS PM1 domains defined by the RASopathy specification, and no statistically significant hotspot evidence was identified for this site.

PM2 This variant is present in gnomAD and therefore is not absent from controls, so PM2_Supporting is not met.

PM6 No presumed de novo report without full parental confirmation was identified for this variant, so PM6 cannot be assigned.

PP1 No segregation data were identified for this variant, so PP1 cannot be applied.

PP3 Available computational evidence does not support a damaging effect.

Benign

BS2 No healthy adult carrier observations meeting the RASopathy point-based BS2 framework were identified for this variant.

BS4 No nonsegregation data were identified for this variant, so BS4 cannot be applied.

BP2 No data were identified showing this variant in cis or trans with another pathogenic RASopathy variant or establishing an alternative molecular explanation under the RASopathy point-based framework.

BP5 No evidence was identified for another molecular finding that would better explain the phenotype, so BP5 cannot be assigned.

N/A · 12 PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BS3 · BP1 · BP3 · BP4

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.77303e-05; MAF= 0.00177%, 27/1522820 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000618111; MAF= 0.06181%, 24/38828 alleles, homozygotes = 0); grpmax FAF= 0.0004261.

v2.1

This variant is present in gnomAD v2.1 (AF= 8.85545e-05; MAF= 0.00886%, 25/282312 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00125452; MAF= 0.12545%, 25/19928 alleles, homozygotes = 0); grpmax FAF= 0.00090025.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.0018% · 27 / 1,522,820
0 hom · FAF 0.043%

East Asian 24 / 38,828	0.062%
Remaining individuals 2 / 56,734	0.0035%
European (non-Finnish) 1 / 1,122,562	8.9e-05%

+ 7 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0089% · 25 / 282,312
0 hom · FAF 0.09%

East Asian

25 / 19,928

0.13%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Benign (3 clinical laboratories) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 164807)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 2 PMIDs not cited in assessment

24033266 ↗ A systematic approach to assessing the clinical significance of genetic variants. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR

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