About NRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NRAS c.31G>A, p.(Ala11Thr)
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM1Moderate
PM1 · moderate
This missense variant affects NRAS residue Ala11, which lies within the P-loop region (amino acids 10-17), a RASopathy VCEP-specified critical and well-established functional domain; this supports PM1 at Moderate strength.
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 Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PM1 moderate; no rule matched the adjudicated criteria.
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
1 / 1,613,858 alleles
gnomAD v4.1: 1 / 1,613,858 alleles. Recorded AF 6.19633e-07. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97627e-06; MAF= 0.00040%, 1/251492 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
No listed criterion applied
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
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: 1 met · 9 not met · 8 not assessed · 10 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.31G>A (p.Ala11Thr) variant has been reported in ClinVar with an expert panel interpretation of uncertain significance and has also been curated in variant-specific cancer resources.
This variant is present at very low frequency in population databases, with 1/251492 alleles in gnomAD v2.1 (AF 0.00040%) and 1/1613858 alleles in gnomAD v4.1 (AF 0.000062%).
The p.Ala11Thr change lies within the NRAS P-loop (amino acids 10-17), a RASopathy VCEP-specified critical functional domain, which supports PM1.
SpliceAI predicts no significant splice impact for this variant (maximum delta score 0.00), the REVEL score is 0.412, and the BayesDel score is 0.00411725; these values do not meet the RASopathy VCEP thresholds for either PP3 or BP4.
No criteria match.
Met · 1
PM1 ModerateThis missense variant affects NRAS residue Ala11, which lies within the P-loop region (amino acids 10-17), a RASopathy VCEP-specified critical and well-established functional domain; this supports PM1 at Moderate strength. Details ▾Hide ▴
Rule
PM1 Moderate for variants in specified critical domains including the P-loop (AA 10-17).
Evidence considered
- Protein consequence p.(Ala11Thr)
- RASopathy VCEP PM1 domain list includes the P-loop at amino acids 10-17
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
Not met · 9 · evaluated, threshold not reached
PS1 Available evidence does not identify a previously established pathogenic variant with the same amino acid change that would support PS1. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant.
Evidence considered
- Reviewed the NRAS RASopathy VCEP framework and the available case materials for same-amino-acid pathogenic evidence
Still missing
- Direct confirmation of any same-amino-acid pathogenic analogue was not identified in the available sources.
Sources
PS3 Published functional literature was identified, but the available materials do not provide a reviewed result from one or more RASopathy VCEP-approved assays for this exact variant that is sufficient to apply PS3. Details ▾Hide ▴
Rule
PS3 requires one approved assay for Supporting or two or more different approved assays for Moderate.
Evidence considered
- Variant-specific functional literature was linked from curated cancer resources
- RASopathy VCEP approved-assay framework was reviewed
Still missing
- Direct review of the full functional data for this exact variant would be needed to determine whether an approved assay result supports PS3.
Sources
PM2 This variant is not absent from population databases. It is present in gnomAD v2.1 at 1/251492 alleles (AF 0.00040%) and in gnomAD v4.1 at 1/1613858 alleles (AF 0.000062%), so the RASopathy VCEP PM2 absence requirement is not met. Details ▾Hide ▴
Rule
PM2 Supporting requires the variant to be absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1 total AF 3.976269622890589e-06
- gnomAD v4.1 total AF 6.196332019297856e-07
Sources
PM4 This variant is a missense substitution and does not cause a protein length change, so PM4 is not met. Details ▾Hide ▴
Rule
PM4 applies to protein length changes such as in-frame indels or stop-loss variants.
Evidence considered
- Protein consequence is p.(Ala11Thr) missense
Sources
PM5 Available evidence does not identify a different pathogenic or likely pathogenic amino acid change at NRAS codon 11 that would support PM5. Details ▾Hide ▴
Rule
PM5 requires a different pathogenic or likely pathogenic residue change at the same codon.
Evidence considered
- Reviewed the codon-specific evidence available in the case materials and VCEP framework
Still missing
- Direct confirmation of any qualifying codon-11 pathogenic missense analogue was not identified in the available sources.
Sources
PP3 For missense variants, the RASopathy VCEP applies PP3 when REVEL is at least 0.7. The REVEL score for this variant is 0.412, which is below that threshold. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the available computational data do not support PP3. Details ▾Hide ▴
Rule
PP3 Supporting for missense variants requires REVEL >= 0.7; splice predictions must also match the disease mechanism if relevant.
Evidence considered
- REVEL 0.412
- SpliceAI max delta 0.00
- BayesDel 0.00411725
Sources
BA1 The RASopathy VCEP BA1 threshold is a filtering allele frequency of at least 0.05%. This variant is far below that threshold, with gnomAD frequencies of 0.00040% in v2.1 and 0.000062% in v4.1, so BA1 is not met. Details ▾Hide ▴
Rule
BA1 requires gnomAD filtering allele frequency >= 0.05%.
Evidence considered
- gnomAD v2.1 AF 0.00040%
- gnomAD v4.1 AF 0.000062%
Sources
BS1 The RASopathy VCEP BS1 threshold is a filtering allele frequency of at least 0.025%. This variant is well below that threshold, with gnomAD frequencies of 0.00040% in v2.1 and 0.000062% in v4.1, so BS1 is not met. Details ▾Hide ▴
Rule
BS1 requires gnomAD filtering allele frequency >= 0.025%.
Evidence considered
- gnomAD v2.1 AF 0.00040%
- gnomAD v4.1 AF 0.000062%
Sources
BP4 For missense variants, the RASopathy VCEP applies BP4 when REVEL is 0.3 or lower. The REVEL score for this variant is 0.412, which is above that threshold, so BP4 is not met. SpliceAI shows no significant splice effect with a maximum delta score of 0.00, but that does not overcome the missense REVEL threshold requirement. Details ▾Hide ▴
Rule
BP4 Supporting for missense variants requires REVEL <= 0.3.
Evidence considered
- REVEL 0.412
- SpliceAI max delta 0.00
- BayesDel 0.00411725
Sources
Not assessed · 8 · no assessment recorded
PS2 No confirmed de novo occurrence with documented maternity and paternity confirmation was identified for this variant. Details ▾Hide ▴
Rule
De novo occurrence scored by the RASopathy VCEP point-based framework.
Evidence considered
- No de novo evidence was captured in the available ClinVar summary or supporting materials
Still missing
- Need case-level parental testing details and phenotype information for any reported proband.
Sources
PS4 This variant has been reported in ClinVar, but no secure count of unrelated affected individuals with this exact variant or case-control enrichment data was identified to support PS4 scoring. Details ▾Hide ▴
Rule
PS4 requires point-based evidence from affected individuals under the RASopathy VCEP framework.
Evidence considered
- ClinVar expert panel record for this exact variant
Still missing
- Need the number of unrelated affected probands and any qualifying point-based PS4 evidence under the RASopathy VCEP framework.
Sources
PM6 No presumed de novo occurrence without full parentage confirmation was identified for this variant. Details ▾Hide ▴
Rule
PM6 is scored with the RASopathy VCEP point-based de novo framework when parentage confirmation is incomplete.
Evidence considered
- No PM6-type de novo information was captured in the available sources
Still missing
- Need case-level reports showing the variant was absent in parents when formal maternity and paternity confirmation was not completed.
Sources
PP1 No segregation data were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
Rule
PP1 requires informative meioses under the RASopathy VCEP framework.
Evidence considered
- No family segregation information was identified in the available sources
Still missing
- Need informative meioses showing co-segregation with a RASopathy phenotype.
Sources
BS2 No evidence was identified showing this variant in a sufficient number of apparently unaffected individuals to support BS2. Details ▾Hide ▴
Rule
BS2 is scored using the RASopathy VCEP point-based framework for unaffected individuals.
Evidence considered
- No unaffected carrier data were identified in the available sources
Still missing
- Need documented unaffected carriers meeting the RASopathy VCEP point-based BS2 framework.
Sources
BS4 No non-segregation data were identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
Rule
BS4 requires informative non-segregation data.
Evidence considered
- No family non-segregation information was identified in the available sources
Still missing
- Need informative family data showing lack of segregation with phenotype.
Sources
BP2 No evidence was identified that this variant occurred with an alternative molecular explanation in cis or trans that would support BP2 scoring. Details ▾Hide ▴
Rule
BP2 is scored using the RASopathy VCEP point-based framework.
Evidence considered
- No cis/trans or alternate-cause data were identified
Still missing
- Need phase information and an alternative molecular cause meeting the RASopathy VCEP point-based framework.
Sources
BP5 No evidence was identified for an alternative molecular cause that would explain the phenotype and support BP5 scoring. Details ▾Hide ▴
Rule
BP5 is scored using the RASopathy VCEP point-based framework.
Evidence considered
- No alternate molecular explanation was identified
Still missing
- Need a documented alternate molecular diagnosis meeting the RASopathy VCEP point-based BP5 framework.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution, not a null variant, and it does not fall into the default PVS1 categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Details ▾Hide ▴
Rule
PVS1 not applicable for this missense variant in the NRAS RASopathy framework.
Evidence considered
- Missense change p.(Ala11Thr)
- Generic PVS1 scaffold did not place this variant in a PVS1-eligible null-variant bucket
Sources
cspec ↗pvs1_variant_assessment
PM3 N/APM3 is not applicable in this RASopathy VCEP framework for this case. Details ▾Hide ▴
PP2 N/APP2 is not applicable in this RASopathy VCEP framework. Details ▾Hide ▴
PP4 N/APP4 is not applicable in this RASopathy VCEP framework. Details ▾Hide ▴
PP5 N/APP5 is not applicable in this RASopathy VCEP framework. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in this RASopathy VCEP framework. Details ▾Hide ▴
BP1 N/AIn this RASopathy VCEP framework, BP1 is intended for truncating loss-of-function variants in genes with primarily gain-of-function disease mechanisms. This variant is missense, so BP1 is not applicable. Details ▾Hide ▴
Rule
BP1 applies here to truncating variants in gain-of-function RASopathy genes.
Evidence considered
- Variant is missense
- not truncating
Sources
BP3 N/ABP3 is not applicable in this RASopathy VCEP framework. Details ▾Hide ▴
BP6 N/ABP6 is not applicable in this RASopathy VCEP framework. Details ▾Hide ▴
BP7 N/AThis variant is missense rather than synonymous or intronic, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous, intronic, or non-coding variants with no predicted splice impact.
Evidence considered
- Protein consequence is missense p.(Ala11Thr)
- SpliceAI max delta 0.00
Sources
Identifiers
- Gene
- NRAS
- Transcript
- NM_002524.4
- Coding (HGVS c.)
- NM_002524.4:c.31G>A
- Protein (HGVS p.)
- NP_002515.1:p.(Ala11Thr)
- GRCh38
- chr1:114716130 C>T
- GRCh37
- chr1:115258751 C>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
1 / 1,613,858 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
1 / 251,492 alleles
AF 3.98e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,858 alleles · 0 hom
| Admixed American1 / 60,026 | 1.7e-05 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 4e-06 · 1 / 251,492 alleles · 0 hom
| Admixed American1 / 34,592 | 2.9e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19633e-07; MAF= 0.00006%, 1/1613858 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66594e-05; MAF= 0.00167%, 1/60026 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97627e-06; MAF= 0.00040%, 1/251492 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 For missense variants, the RASopathy VCEP applies PP3 when REVEL is at least 0.7. The REVEL score for this variant is 0.412, which is below that threshold. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the available computational data do not support PP3. Details ▾Hide ▴
Rule
PP3 Supporting for missense variants requires REVEL >= 0.7; splice predictions must also match the disease mechanism if relevant.
Evidence considered
- REVEL 0.412
- SpliceAI max delta 0.00
- BayesDel 0.00411725
Sources
BP4 For missense variants, the RASopathy VCEP applies BP4 when REVEL is 0.3 or lower. The REVEL score for this variant is 0.412, which is above that threshold, so BP4 is not met. SpliceAI shows no significant splice effect with a maximum delta score of 0.00, but that does not overcome the missense REVEL threshold requirement. Details ▾Hide ▴
Rule
BP4 Supporting for missense variants requires REVEL <= 0.3.
Evidence considered
- REVEL 0.412
- SpliceAI max delta 0.00
- BayesDel 0.00411725
Sources
BP7 N/AThis variant is missense rather than synonymous or intronic, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous, intronic, or non-coding variants with no predicted splice impact.
Evidence considered
- Protein consequence is missense p.(Ala11Thr)
- SpliceAI max delta 0.00
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.412. BayesDel score = 0.00411725.
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
1 / 1,613,858 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/561350/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-115258751-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-114716130-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002524.4%3Ac.31G%…
- OncoKB ↗www.oncokb.org/gene/NRAS/A11T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=116668869
- 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= 6.19633e-07; MAF= 0.00006%, 1/1613858 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66594e-05; MAF= 0.00167%, 1/60026 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.97627e-06; MAF= 0.00040%, 1/251492 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.412. BayesDel score = 0.00411725.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Neutral; curated oncogenicity label: Likely Neutral.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54738286, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.