Classification rationale

BS1BP6 Likely Benign

NRAS c.112-8A>G

The NRAS c.112-8A>G (p.?) variant has been reported in ClinVar, where the aggregate classification is likely benign and expert panel review is present.¹ This variant is present in population databases, with gnomAD v2.1 total AF 0.02558% and grpmax FAF 0.03711%, and gnomAD v4.1 total AF 0.03946% and grpmax FAF 0.04727%, which is above the NRAS RASopathy BS1 threshold of 0.025% but below the BA1 threshold of 0.05%.² SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.02, which does not support a deleterious splicing prediction.³

BS1 + BP6 → Likely 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 · 2 applied · 13 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 · 2

Strength Supporting Moderate Strong Very strong

BS1 strong Benign

BS1 requires a gnomAD filtering allele frequency of at least 0.025%. The observed grpmax FAF is 0.03711% in gnomAD v2.1 and 0.04727% in gnomAD v4.1, both above the 0.025% threshold, so BS1 is met at strong strength.

gnomAD v2.1 grpmax FAF exceeds 0.025%gnomAD v4.1 grpmax FAF exceeds 0.025%

cspec ↗gnomad_v2 ↗gnomad_v4 ↗

BP6 supporting Benign

Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely benign.

RASopathy VCEP marks BP6 as not applicableClinVar expert panel classification

cspec ↗clinvar ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PS2 No confirmed de novo occurrence with maternity and paternity established was identified.

PS3 No approved functional or RNA assay result for this specific splice-region variant was identified.

PS4 This variant is present in population databases and no affected-case enrichment data were identified.

PM2 PM2_Supporting requires absence from gnomAD.

PM6 No assumed de novo report for this variant was identified.

PP1 No segregation data were identified for this variant.

PP3 For splice prediction, PP3 requires a predicted splicing outcome that matches the disease mechanism.

Benign

BA1 BA1 requires a gnomAD filtering allele frequency of at least 0.05%.

BS2 Although this variant is present in population databases, no phenotype-qualified healthy adult observations or point-based evidence meeting the RASopathy BS2 specification were identified.

BS4 No nonsegregation data were identified for this variant.

BP2 No evidence was identified that this variant occurs in cis or trans with another established pathogenic RASopathy variant or that the required point-based alternative-molecular-cause framework is satisfied.

BP5 No alternative molecular explanation for the phenotype in another gene, and no phenotype-based evidence against this variant, were identified.

BP7 This noncanonical intronic variant has a low SpliceAI maximum delta score of 0.02, which predicts no significant splice impact.

N/A · 13 PVS1 · PS1 · PM1 · 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= 0.000394632; MAF= 0.03946%, 529/1340490 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000510694; MAF= 0.05107%, 499/977102 alleles, homozygotes = 0); grpmax FAF= 0.00047274.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000255817; MAF= 0.02558%, 71/277542 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000487061; MAF= 0.04871%, 62/127294 alleles, homozygotes = 0); grpmax FAF= 0.00037107.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.039% · 529 / 1,340,490
0 hom · FAF 0.047%

European (non-Finnish) 499 / 977,102	0.051%
European (Finnish) 12 / 48,214	0.025%
Remaining individuals 12 / 48,538	0.025%
African/African American 6 / 66,904	0.009%

+ 6 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.026% · 71 / 277,542
0 hom · FAF 0.037%

European (non-Finnish) 62 / 127,294	0.049%
European (Finnish) 5 / 24,796	0.02%
Remaining individuals 1 / 7,036	0.014%
African/African American 3 / 24,648	0.012%

+ 4 not observed (Admixed American, Ashkenazi Jewish, East Asian, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Likely Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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