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LYFE SCIENCES
Project: HERA
NM_002524.4:c.176C>A
p.Ala59Asp  ·  NRAS
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Classification rationale
1

The NRAS c.176C>A (p.Ala59Asp, p.A59D) variant has been observed in somatic cancers in COSMIC (COSV54738004, 12 occurrences) and has been reported in ClinVar as Likely pathogenic by 1 clinical laboratory.

cosmic ↗ clinvar ↗
2

This variant is absent from gnomAD controls, with 0/1,611,062 alleles in gnomAD v4.1 and no observation in gnomAD v2.1, supporting PM2_Supporting and arguing against a benign population frequency threshold.

gnomad_v2 ↗ gnomad_v4 ↗
3

The variant is located in the NRAS Switch II domain (amino acids 57-64), a critical and well-established functional region specified for PM1 in the NRAS RASopathy criteria, but no ClinGen-approved variant-specific functional assay result was identified to apply PS3.

cspec ↗
4

Computational evidence supports a deleterious missense effect because the REVEL score is 0.837, above the PP3 threshold of 0.7, while SpliceAI predicts no significant splice effect with a maximum delta score of 0.01.

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
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Rule
—
Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1Absent from gnomAD v2.1.
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1611062 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74784 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Gain-of-function.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54738004, n = 12 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueA59
Hotspots ↗