About NRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NRAS c.368G>A, p.(Arg123Lys)
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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the NRAS RASopathy VCEP PM2 threshold requiring absence from controls.
PP3Supporting
PP3 · supporting
Computational evidence supports a deleterious effect. REVEL is 0.759, which is above the NRAS RASopathy VCEP PP3 threshold of 0.7, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the available BayesDel score is 0.166482, which is directionally consistent with a damaging missense prediction.
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: PM2 supporting, PP3 supporting; 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
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 did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NRAS, a GTPase, is mutated in a diverse range of cancers, most frequently in melanoma and thyroid cancer.
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: 2 met · 7 not met · 8 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.368G>A (p.Arg123Lys) variant has not been observed in COSMIC and is reported in ClinVar as uncertain significance, including an expert panel submission from the ClinGen RASopathy Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in the general population and meeting the NRAS RASopathy VCEP PM2_Supporting rule.
The reviewed RASopathy VCEP functional study materials identify approved assay types for NRAS, but no variant-specific approved assay result for p.Arg123Lys was identified, so PS3 is not currently supported.
In silico evidence supports a deleterious missense effect, with REVEL 0.759 above the NRAS RASopathy VCEP PP3 threshold of 0.7, BayesDel 0.166482 directionally consistent with a damaging prediction, and SpliceAI predicting no significant splice impact with a maximum delta score of 0.00.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the NRAS RASopathy VCEP PM2 threshold requiring absence from controls. Details ▾Hide ▴
Rule
PM2 Supporting: the variant must be absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
Sources
PP3 SupportingComputational evidence supports a deleterious effect. REVEL is 0.759, which is above the NRAS RASopathy VCEP PP3 threshold of 0.7, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the available BayesDel score is 0.166482, which is directionally consistent with a damaging missense prediction. Details ▾Hide ▴
Rule
PP3 Supporting for missense variants: REVEL >= 0.7; for splicing, the predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.759
- SpliceAI max delta 0.00
- BayesDel 0.166482
Sources
Not met · 7 · evaluated, threshold not reached
PS1 No previously established pathogenic variant producing the same amino acid change, p.Arg123Lys, was identified in the reviewed evidence, so PS1 is not supported. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant, including analogous positions in specified RAS genes.
Evidence considered
- ClinVar record for NRAS p.Arg123Lys is Uncertain Significance
- No reviewed same-amino-acid pathogenic comparison identified
Still missing
- Confirmation from a comprehensive cross-gene residue review would be needed if new same-amino-acid pathogenic evidence emerges.
Sources
PM1 Residue Arg123 is outside the NRAS RASopathy VCEP PM1 domains (P-loop amino acids 10-17, Switch I amino acids 25-40, Switch II amino acids 57-64, and SAK amino acids 145-156), so PM1 is not met. Details ▾Hide ▴
Rule
PM1 is limited to specified critical functional domains and is not applied to specific residues outside those domains.
Evidence considered
- Protein consequence p.Arg123Lys
- VCEP PM1 domains: 10-17
- 25-40
- 57-64
- 145-156
Sources
PM5 No different pathogenic or likely pathogenic missense change at codon 123 was identified in the reviewed evidence, so PM5 is not supported. Details ▾Hide ▴
Rule
PM5 Moderate requires one pathogenic or likely pathogenic residue change at the same codon; PM5 Strong requires two such changes observed in at least 5 probands.
Evidence considered
- Reviewed ClinVar evidence for codon 123 did not identify an established pathogenic alternate residue change
Still missing
- A validated pathogenic or likely pathogenic alternative missense change at the same codon would be needed for PM5.
Sources
BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the NRAS RASopathy VCEP BA1 threshold of 0.05%, so BA1 is not met. Details ▾Hide ▴
Rule
BA1: gnomAD filtering allele frequency >= 0.05%.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- BA1 threshold: >=0.05%
Sources
BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the NRAS RASopathy VCEP BS1 threshold of 0.025%, so BS1 is not met. Details ▾Hide ▴
Rule
BS1: gnomAD filtering allele frequency >= 0.025%.
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: absent
- BS1 threshold: >=0.025%
Sources
BS2 No observations of this variant in unaffected individuals suitable for NRAS RASopathy VCEP BS2 scoring were identified, so BS2 is not met. Details ▾Hide ▴
BP4 Computational evidence does not support a benign interpretation. REVEL is 0.759, which is above the NRAS RASopathy VCEP BP4 benign threshold of 0.3, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the available BayesDel score of 0.166482 does not provide benign support. Details ▾Hide ▴
Rule
BP4 Supporting for missense variants: REVEL <= 0.3.
Evidence considered
- REVEL 0.759
- SpliceAI max delta 0.00
- BayesDel 0.166482
- BP4 threshold: REVEL <= 0.3
Sources
Not assessed · 8 · no assessment recorded
PS2 No confirmed de novo occurrence with maternity and paternity established was identified for this variant, so PS2 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
De novo evidence is scored by the RASopathy VCEP using the SVI point-based framework.
Evidence considered
- No de novo data provided in reviewed case materials
- ClinVar summary does not provide usable PS2 point-based evidence
Still missing
- Case-level trio data with confirmed maternity and paternity
- Phenotype details sufficient for VCEP point assignment
Sources
PS3 The reviewed RASopathy VCEP functional study materials list approved assay types for NRAS, but no variant-specific approved assay result for p.Arg123Lys was identified, so PS3 is not currently supported. Details ▾Hide ▴
Rule
PS3 Supporting requires one approved assay; PS3 Moderate requires two or more different approved assays.
Evidence considered
- Approved assay framework for NRAS exists
- No variant-specific approved assay result identified for p.Arg123Lys
Still missing
- Variant-specific result from one approved assay for PS3_Supporting
- Variant-specific results from two or more different approved assays for PS3_Moderate
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 This variant is absent from gnomAD, satisfying the PM2 prerequisite for PS4 consideration, but no usable count of unrelated affected individuals or point-based case evidence was identified, so PS4 cannot be assessed. Details ▾Hide ▴
Rule
PS4 uses point-based case evidence in the RASopathy VCEP and requires PM2_Supporting first.
Evidence considered
- Absent from gnomAD v2.1
- Absent from gnomAD v4.1
- ClinVar summary does not provide usable PS4 point totals
Still missing
- Count of unrelated affected probands with this variant
- Phenotype details and case-point data needed for VCEP PS4 scoring
Sources
PM6 No unconfirmed de novo report with sufficient phenotype context was identified for this variant, so PM6 cannot be assessed from the available evidence. Details ▾Hide ▴
Rule
PM6 uses the RASopathy VCEP point-based de novo framework when parentage is not fully confirmed.
Evidence considered
- No usable PM6-level de novo evidence identified
Still missing
- Case-level report describing de novo occurrence without full parentage confirmation
- Phenotype details needed for VCEP point assignment
Sources
PP1 No segregation data were identified for this variant, so PP1 cannot be assessed. Details ▾Hide ▴
BS4 No non-segregation data or unaffected carrier relatives were identified for this variant, so BS4 cannot be assessed. Details ▾Hide ▴
BP2 No evidence was identified that this variant occurs in cis or trans with an alternative pathogenic RASopathy variant with sufficient phenotype context, so BP2 cannot be assessed. Details ▾Hide ▴
BP5 No alternative molecular explanation or phenotype-discordant diagnosis was identified that would support BP5, so this criterion cannot be assessed. Details ▾Hide ▴
Rule
BP5 uses VCEP point-based scoring for an alternative molecular basis of disease or phenotype inconsistency.
Evidence considered
- No usable BP5 evidence identified
Still missing
- Documented alternative cause of the phenotype in another gene or a clearly non-RASopathy explanation
Sources
Not applicable · 11· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the NRAS RASopathy VCEP does not apply PVS1 to this variant type. The generic PVS1 scaffold also indicates that this change does not fall into a null-variant category such as nonsense, frameshift, or canonical splice-site loss. Details ▾Hide ▴
Rule
PVS1 not applicable for this VCEP; generic scaffold not triggered for this missense variant.
Evidence considered
- Missense change p.Arg123Lys/p.R123K
- Generic PVS1 scaffold: not a null-variant bucket
Sources
cspec ↗pvs1_variant_assessment
PM3 N/APM3 is not applicable in the NRAS RASopathy VCEP framework. Details ▾Hide ▴
Rule
PM3 not applicable.
Evidence considered
- Criterion designated not applicable by NRAS VCEP
Sources
PM4 N/AThis is a missense substitution and does not cause an in-frame insertion, in-frame deletion, or stop-loss change, so PM4 is not applicable. Details ▾Hide ▴
Rule
PM4 applies to in-frame indels and stop-loss variants.
Evidence considered
- Variant consequence p.Arg123Lys missense
Sources
PP2 N/APP2 is not applicable in the NRAS RASopathy VCEP framework. Details ▾Hide ▴
Rule
PP2 not applicable.
Evidence considered
- Criterion designated not applicable by NRAS VCEP
Sources
PP4 N/APP4 is not applicable in the NRAS RASopathy VCEP framework because phenotype-based evidence is handled through other criteria such as PS4. Details ▾Hide ▴
Rule
PP4 not applicable, see PS4.
Evidence considered
- Criterion designated not applicable by NRAS VCEP
Sources
PP5 N/APP5 is not used in this VCEP framework. Details ▾Hide ▴
Rule
PP5 not for use as recommended by the ClinGen SVI VCEP Review Committee.
Evidence considered
- Criterion designated not applicable by NRAS VCEP
Sources
BS3 N/ABS3 is not applicable in the NRAS RASopathy VCEP framework. Details ▾Hide ▴
Rule
BS3 not applicable.
Evidence considered
- Criterion designated not applicable by NRAS VCEP
Sources
BP1 N/ABP1 in the NRAS RASopathy VCEP framework is reserved for truncating or other loss-of-function variant types in genes where gain-of-function missense variants are the primary disease mechanism. This variant is missense, so BP1 is not applicable. Details ▾Hide ▴
Rule
BP1 applies to truncating/LOF-type variants under this RASopathy-specific specification.
Evidence considered
- Variant consequence p.Arg123Lys missense
- BP1 reserved for truncating/LOF-type variants in this framework
Sources
cspec ↗pvs1_variant_assessment
BP3 N/ABP3 is not applicable in the NRAS RASopathy VCEP framework. Details ▾Hide ▴
Rule
BP3 not applicable.
Evidence considered
- Criterion designated not applicable by NRAS VCEP
Sources
BP6 N/ABP6 is not used in this VCEP framework. Details ▾Hide ▴
Rule
BP6 not for use as recommended by the ClinGen SVI VCEP Review Committee.
Evidence considered
- Criterion designated not applicable by NRAS VCEP
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous, certain intronic, or non-coding variants with no predicted splice impact.
Evidence considered
- Variant consequence p.Arg123Lys missense
- SpliceAI max delta 0.00
Sources
Identifiers
- Gene
- NRAS
- Transcript
- NM_002524.4
- Coding (HGVS c.)
- NM_002524.4:c.368G>A
- Protein (HGVS p.)
- NP_002515.1:p.(Arg123Lys)
- GRCh38
- chr1:114709651 C>T
- GRCh37
- chr1:115252272 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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
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 effect. REVEL is 0.759, which is above the NRAS RASopathy VCEP PP3 threshold of 0.7, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the available BayesDel score is 0.166482, which is directionally consistent with a damaging missense prediction. Details ▾Hide ▴
Rule
PP3 Supporting for missense variants: REVEL >= 0.7; for splicing, the predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.759
- SpliceAI max delta 0.00
- BayesDel 0.166482
Sources
BP4 Computational evidence does not support a benign interpretation. REVEL is 0.759, which is above the NRAS RASopathy VCEP BP4 benign threshold of 0.3, SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the available BayesDel score of 0.166482 does not provide benign support. Details ▾Hide ▴
Rule
BP4 Supporting for missense variants: REVEL <= 0.3.
Evidence considered
- REVEL 0.759
- SpliceAI max delta 0.00
- BayesDel 0.166482
- BP4 threshold: REVEL <= 0.3
Sources
BP7 N/AThis is not a synonymous, intronic, or non-coding variant, so BP7 is not applicable. Details ▾Hide ▴
Rule
BP7 applies to synonymous, certain intronic, or non-coding variants with no predicted splice impact.
Evidence considered
- Variant consequence p.Arg123Lys missense
- 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 = 0.759. BayesDel score = 0.166482.
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
Captured gnomAD v4.1 source record
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/164809/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-115252272-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-114709651-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002524.4%3Ac.368G…
- OncoKB ↗www.oncokb.org/gene/NRAS/R123K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NRAS+c.368G%3EA
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) 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 = 0.759. BayesDel score = 0.166482.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. NRAS, a GTPase, is mutated in a diverse range of cancers, most frequently in melanoma and thyroid cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.