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 ↗

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

NRAS NM_002524.4

Fetching transcript structure from UCSC…

Applied criteria · 2 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= 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