About NRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NRAS c.176C>A, p.(Ala59Asp)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen NRAS VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Moderate
PM1 · moderate
The p.Ala59Asp missense change lies within the NRAS Switch II region (amino acids 57-64), which is a critical and well-established functional domain specified for PM1 in the NRAS RASopathy criteria.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD controls, with 0/1,611,062 alleles in gnomAD v4.1 and no observation in gnomAD v2.1, which meets the NRAS PM2_Supporting rule requiring absence from controls.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious protein effect because the REVEL score is 0.837, which is above the NRAS PP3 threshold of 0.7, while SpliceAI shows no meaningful splice effect (max delta score 0.01), supporting a missense rather than splice mechanism.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS v2.3.0 final-classification framework; applied criteria are PM1 at Moderate strength, PM2 at Supporting strength, and PP3 at Supporting strength, a combination that does not meet any Pathogenic, Likely Pathogenic, Likely Benign, or Benign rule and therefore remains Uncertain significance.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
0 / 1,611,062 alleles
gnomAD v4.1: 0 / 1,611,062 alleles. Recorded AF 0. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Gain-of-function.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen NRAS VCEP v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 3 not met · 11 not assessed · 11 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
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.
No criteria match.
Met · 3
PM1 ModerateThe p.Ala59Asp missense change lies within the NRAS Switch II region (amino acids 57-64), which is a critical and well-established functional domain specified for PM1 in the NRAS RASopathy criteria. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0 PM1 Moderate: applicable only to P-loop (AA10-17), SW1 (AA25-40), SW2 (AA57-64), and SAK (AA145-156).
Evidence considered
- NRAS CSPEC lists Switch II (AA 57-64) as a PM1 domain.
- Local PM1 domain alignment material shows the Switch II domain mapped across RAS proteins.
- Ala59 falls within AA 57-64.
Sources
cspec ↗vcep_a_l_i_g_n_m_e_n_t___w_i_t_h___p_m_1___d_o_m_a_i_n_s___p_p_t_x
PM2 SupportingThis variant is absent from gnomAD controls, with 0/1,611,062 alleles in gnomAD v4.1 and no observation in gnomAD v2.1, which meets the NRAS PM2_Supporting rule requiring absence from controls. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0 PM2_Supporting: variant must be absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1: absent.
- gnomAD v4.1: total AC 0, AN 1611062, AF 0.0; highest subpopulation AC 0, AN 74784, AF 0.0.
Sources
PP3 SupportingComputational evidence supports a deleterious protein effect because the REVEL score is 0.837, which is above the NRAS PP3 threshold of 0.7, while SpliceAI shows no meaningful splice effect (max delta score 0.01), supporting a missense rather than splice mechanism. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0 PP3 Supporting: REVEL >=0.7 for missense variants; for splicing impact, the predicted outcome must match disease mechanism.
Evidence considered
- REVEL score 0.837.
- SpliceAI max delta score 0.01.
Sources
Not met · 3 · evaluated, threshold not reached
BA1 Population frequency does not meet BA1 because the gnomAD v4.1 allele frequency is 0.0% (0/1,611,062), which is below the BA1 threshold of 0.05%. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0 BA1: filtering allele frequency >=0.05%.
Evidence considered
- gnomAD v4.1 total AF 0.0%, AC 0, AN 1611062.
Sources
BS1 Population frequency does not meet BS1 because the gnomAD v4.1 allele frequency is 0.0% (0/1,611,062), which is below the BS1 threshold of 0.025%. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0 BS1: filtering allele frequency >=0.025%.
Evidence considered
- gnomAD v4.1 total AF 0.0%, AC 0, AN 1611062.
Sources
BP4 Computational evidence does not support BP4 because the REVEL score is 0.837, which is above the benign threshold of 0.3. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0 BP4: REVEL <=0.3 for missense variants.
Evidence considered
- REVEL score 0.837.
Sources
Not assessed · 11 · no assessment recorded
PS1 No evidence was identified showing that this nucleotide change produces the same amino acid substitution as a previously established pathogenic variant. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- ClinVar shows this exact variant as Likely pathogenic, but the available evidence does not document a different nucleotide change causing the same amino acid substitution.
Still missing
- A codon-specific review of established pathogenic alternate nucleotide changes leading to p.Ala59Asp would be needed.
Sources
PS2 No confirmed de novo occurrence with phenotype and parental testing information was identified, so PS2 cannot be scored. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: point-based de novo scoring.
Evidence considered
- No de novo case-level data were identified in the available materials.
Still missing
- Documented maternity and paternity confirmation and phenotype details would be needed.
Sources
PS3 Approved functional assay types for NRAS are listed by the RASopathy VCEP, but no variant-specific result for p.Ala59Asp was identified in the available functional materials, so PS3 is not applied. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: PS3_Supporting for one approved assay; PS3_Moderate for two or more different approved assays.
Evidence considered
- The VCEP functional workbook lists approved NRAS assay classes and PMIDs but no row explicitly identifying p.Ala59Asp.
- OncoKB describes the variant as Likely Oncogenic with likely gain-of-function, which is supportive biologic context but is not a ClinGen-approved PS3 assay result.
Still missing
- Variant-specific results from one or more ClinGen-approved NRAS functional assays would be needed.
Sources
PS4 This variant has been reported in ClinVar and in somatic cancers in COSMIC, but no germline case-count or case-control data were identified to assign the RASopathy point-based PS4 criterion. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: PS4 is point based (Supporting at >=1 point, Moderate at >=3 points, Strong at >=5 points).
Evidence considered
- ClinVar reports the variant as Likely pathogenic from 1 clinical laboratory.
- COSMIC reports somatic occurrence 12 times.
- No germline enrichment or qualifying proband count was identified.
Still missing
- Germline proband counts and phenotype-based PS4 point assignment are needed.
Sources
PM5 No codon-specific evidence was identified showing a different established pathogenic missense change at NRAS codon 59 or an applicable analogous residue position sufficient to assign PM5. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: PM5 Moderate for 1 pathogenic/likely pathogenic residue change at the same codon; PM5 Strong for >=2 different pathogenic/likely pathogenic residue changes at the same codon observed in >=5 probands.
Evidence considered
- Available materials did not document another established pathogenic residue change at the same codon.
Still missing
- A targeted codon-59 and analogous-residue review across the specified RAS genes would be needed.
Sources
PM6 No assumed de novo case information without confirmed parentage was identified, so PM6 cannot be scored. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: PM6 is point based (Supporting 0.5 point, Moderate 1 point, Strong 2 points).
Evidence considered
- No qualifying PM6 case data were identified in the available materials.
Still missing
- Case-level de novo data without full parental confirmation would be needed for PM6 scoring.
Sources
PP1 No segregation data were identified, so PP1 is not met. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: PP1 Supporting at >=3 informative meioses, Moderate at >=5, Strong at >=7.
Evidence considered
- No family segregation data were identified.
Still missing
- Informative meioses demonstrating segregation would be needed.
Sources
cspec ↗literature_pass
BS2 No data were identified showing this variant in unaffected individuals in a manner that would support BS2. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: BS2 is point based for unaffected observations.
Evidence considered
- The variant is absent from gnomAD and no unaffected carrier evidence was identified.
Still missing
- Well-phenotyped unaffected carrier data would be needed.
Sources
BS4 No non-segregation data were identified, so BS4 is not met. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0 BS4: requires one informative meiosis.
Evidence considered
- No family non-segregation evidence was identified.
Still missing
- Informative non-segregation evidence would be needed.
Sources
cspec ↗literature_pass
BP2 No data were identified showing this variant in cis or trans with an alternative molecular explanation for the phenotype, so BP2 is not applied. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0 BP2: point-based benign evidence from phase with another pathogenic variant or alternative molecular cause.
Evidence considered
- No qualifying BP2 observations were identified.
Still missing
- Phase data and an alternative molecular diagnosis would be needed.
Sources
cspec ↗literature_pass
BP5 No evidence was identified for an alternate molecular basis explaining the phenotype independent of this variant, so BP5 is not applied. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0 BP5: point-based benign evidence from an alternative molecular explanation.
Evidence considered
- No qualifying BP5 evidence was identified.
Still missing
- A documented alternative molecular diagnosis would be needed.
Sources
cspec ↗literature_pass
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis missense variant does not create a predicted loss-of-function allele, and the NRAS RASopathy specification lists PVS1 as not applicable. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: PVS1 not applicable.
Evidence considered
- PVS1 applicability is listed as not applicable in the NRAS RASopathy specification.
- The variant-specific PVS1 assessment states that c.176C>A does not fall into nonsense, frameshift, or canonical splice-site null-variant categories.
Sources
PM3 N/APM3 is not applicable in the NRAS RASopathy specification. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: PM3 not applicable.
Evidence considered
- PM3 applicability is listed as not applicable in the NRAS specification.
Sources
PM4 N/AThis is a missense substitution and does not change protein length, so PM4 is not applicable. Details ▾Hide ▴
Rule
PM4 applies to protein length changes, not missense substitutions.
Evidence considered
- c.176C>A predicts p.Ala59Asp, a missense substitution without protein length change.
Sources
PP2 N/APP2 is not applicable in the NRAS RASopathy specification. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: PP2 not applicable.
Evidence considered
- PP2 applicability is listed as not applicable in the NRAS specification.
Sources
PP4 N/APP4 is not applicable in the NRAS RASopathy specification. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: PP4 not applicable.
Evidence considered
- PP4 applicability is listed as not applicable in the NRAS specification.
Sources
PP5 N/APP5 is not applicable in the NRAS RASopathy specification. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: PP5 not applicable.
Evidence considered
- PP5 applicability is listed as not applicable in the NRAS specification.
Sources
BS3 N/ABS3 is not applicable in the NRAS RASopathy specification. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: BS3 not applicable.
Evidence considered
- BS3 applicability is listed as not applicable in the NRAS specification.
Sources
BP1 N/AThis criterion is reserved in the NRAS RASopathy specification for truncating variants in a gain-of-function disease context and does not apply to this missense variant. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0 BP1: use for truncating variants in genes without established loss-of-function correlation to disease.
Evidence considered
- c.176C>A is a missense variant predicting p.Ala59Asp.
Sources
BP3 N/ABP3 is not applicable in the NRAS RASopathy specification. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: BP3 not applicable.
Evidence considered
- BP3 applicability is listed as not applicable in the NRAS specification.
Sources
BP6 N/ABP6 is not applicable in the NRAS RASopathy specification. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0: BP6 not applicable.
Evidence considered
- BP6 applicability is listed as not applicable in the NRAS specification.
Sources
BP7 N/ABP7 applies to synonymous, intronic, or non-coding variants with no predicted splice impact and does not apply to this missense variant. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0 BP7: synonymous/intronic/non-coding variants with no splice impact.
Evidence considered
- c.176C>A is a missense variant predicting p.Ala59Asp.
Sources
Identifiers
- Gene
- NRAS
- Transcript
- NM_002524.4
- Coding (HGVS c.)
- NM_002524.4:c.176C>A
- Protein (HGVS p.)
- NP_002515.1:p.(Ala59Asp)
- GRCh38
- chr1:114713914 G>T
- GRCh37
- chr1:115256535 G>T
Gene diagram
Every interpreted variant in NRAS, mapped onto the exon structure of NM_002524.4. Select a row to find it on the plot.
NRASNM_002524.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in NRAS
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
0 / 1,611,062 alleles
AF 0 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0 · 0 / 1,611,062 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.
Statements
gnomAD v4.1
This 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 v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingComputational evidence supports a deleterious protein effect because the REVEL score is 0.837, which is above the NRAS PP3 threshold of 0.7, while SpliceAI shows no meaningful splice effect (max delta score 0.01), supporting a missense rather than splice mechanism. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0 PP3 Supporting: REVEL >=0.7 for missense variants; for splicing impact, the predicted outcome must match disease mechanism.
Evidence considered
- REVEL score 0.837.
- SpliceAI max delta score 0.01.
Sources
BP4 Computational evidence does not support BP4 because the REVEL score is 0.837, which is above the benign threshold of 0.3. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0 BP4: REVEL <=0.3 for missense variants.
Evidence considered
- REVEL score 0.837.
Sources
BP7 N/ABP7 applies to synonymous, intronic, or non-coding variants with no predicted splice impact and does not apply to this missense variant. Details ▾Hide ▴
Rule
NRAS CSPEC v2.3.0 BP7: synonymous/intronic/non-coding variants with no splice impact.
Evidence considered
- c.176C>A is a missense variant predicting p.Ala59Asp.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
0 / 1,611,062 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243109
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/812886/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-115256535-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-114713914-G-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002524.4%3Ac.176C…
- OncoKB ↗www.oncokb.org/gene/NRAS/A59D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=116671911
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This 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 v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Likely pathogenic (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
OncoKB classifies this variant as Likely Oncogenic; biological effect: Likely Gain-of-function.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54738004, n = 12 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.