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 ↗

Gene diagram · NM_002524.4 · variants mapped to exon structure

NRAS NM_002524.4

Fetching transcript structure from UCSC…

Applied criteria · 4 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 · 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