About NRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NRAS c.71T>A, p.(Ile24Asn)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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: 6
Benign evidence criteria: 0
Pathogenic criteria applied · 6
PS3Supporting
PS3 · supporting
In expert-panel-reviewed functional evidence, RAS activation assays in 293T cells showed mildly increased GTP-bound RAS with enhanced MAPK phosphorylation, and a zebrafish model showed developmental and craniofacial defects that were rescued by MEK inhibition. This supports an abnormal gain-of-function effect consistent with the NRAS RASopathy mechanism.
PS4Moderate
PS4 · moderate
This variant has been reported in 4 probands with features of RASopathy in expert-panel-reviewed evidence, which the NRAS RASopathy expert panel used to apply PS4 at Moderate strength.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the NRAS RASopathy requirement for PM2 at Supporting strength.
PM6Strong
PM6 · strong
Expert-panel-reviewed evidence reports this variant as de novo in 2 individuals with features of RASopathy, but with unconfirmed parental relationships. Under the NRAS RASopathy point-based framework, this was used to apply PM6 at Strong strength.
PP3Supporting
PP3 · supporting
For this missense variant, the REVEL score is 0.863, which is above the NRAS RASopathy PP3 threshold of 0.7. SpliceAI predicts no splice effect with a maximum delta score of 0.00, supporting interpretation as a missense effect rather than a splicing mechanism. BayesDel is 0.159947 and does not contradict a damaging missense interpretation.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule11 (1 Pathogenic.Strong + 1 Pathogenic.Moderate) with applied criteria: PS3 supporting, PS4 moderate, PM2 supporting, PM6 strong, PP3 supporting, PP5 supporting; maps to Likely Pathogenic.
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.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
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: 6 met · 5 not met · 7 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.71T>A (p.Ile24Asn) variant has been reported in ClinVar and is classified as Likely Pathogenic by the ClinGen RASopathy expert panel.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity under the NRAS RASopathy framework.
In expert-panel-reviewed functional evidence, RAS activation assays showed mildly increased GTP-bound RAS with enhanced MAPK phosphorylation, and a zebrafish model showed developmental and craniofacial defects that were rescued by MEK inhibition, supporting an abnormal gain-of-function effect.
Computational evidence supports a damaging missense effect, with REVEL 0.863 above the PP3 threshold of 0.7, SpliceAI showing no significant splice impact with a maximum delta score of 0.00, and BayesDel 0.159947.
No criteria match.
Met · 6
PS3 SupportingIn expert-panel-reviewed functional evidence, RAS activation assays in 293T cells showed mildly increased GTP-bound RAS with enhanced MAPK phosphorylation, and a zebrafish model showed developmental and craniofacial defects that were rescued by MEK inhibition. This supports an abnormal gain-of-function effect consistent with the NRAS RASopathy mechanism. Details ▾Hide ▴
Rule
PS3 Supporting: one approved assay.
Evidence considered
- ClinVar expert-panel summary reports abnormal RAS activation and MAPK signaling plus a supportive zebrafish model.
- The VCEP functional-study file lists approved NRAS assay types including RAS activation and downstream signaling assays.
Still missing
- Direct review of the underlying primary functional paper would further confirm assay details and strength.
Sources
PS4 ModerateThis variant has been reported in 4 probands with features of RASopathy in expert-panel-reviewed evidence, which the NRAS RASopathy expert panel used to apply PS4 at Moderate strength. Details ▾Hide ▴
Rule
Point-based case enrichment framework for PS4 in the NRAS RASopathy specification.
Evidence considered
- ClinVar expert-panel summary states 4 probands with RASopathy and PS4_Moderate.
Still missing
- Independent verification of the individual case reports and point assignments would strengthen the evidence base.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the NRAS RASopathy requirement for PM2 at Supporting strength. Details ▾Hide ▴
Rule
PM2 Supporting: variant absent from controls (gnomAD).
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
PM6 StrongExpert-panel-reviewed evidence reports this variant as de novo in 2 individuals with features of RASopathy, but with unconfirmed parental relationships. Under the NRAS RASopathy point-based framework, this was used to apply PM6 at Strong strength. Details ▾Hide ▴
Rule
PM6 strength is assigned using the RASopathy point-based de novo framework.
Evidence considered
- ClinVar expert-panel summary states 2 de novo occurrences with unconfirmed parental relationships and PM6_Strong.
Still missing
- Direct review of the original case records would clarify parental testing details and phenotype specificity.
Sources
PP3 SupportingFor this missense variant, the REVEL score is 0.863, which is above the NRAS RASopathy PP3 threshold of 0.7. SpliceAI predicts no splice effect with a maximum delta score of 0.00, supporting interpretation as a missense effect rather than a splicing mechanism. BayesDel is 0.159947 and does not contradict a damaging missense interpretation. Details ▾Hide ▴
Rule
PP3 Supporting for missense variants when REVEL is at least 0.7; for splicing, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.863.
- SpliceAI max delta 0.00.
- BayesDel 0.159947.
Sources
PP5 SupportingExpert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely pathogenic. Details ▾Hide ▴
Not met · 5 · evaluated, threshold not reached
PS2 Available evidence describes de novo occurrences with unconfirmed parental relationships, so confirmed maternity and paternity were not established for PS2. Details ▾Hide ▴
Rule
De novo in a patient with the disease and no family history, with maternity and paternity confirmed.
Evidence considered
- ClinVar expert-panel summary states de novo occurrences had unconfirmed parental relationships.
Still missing
- A primary report or submitter record with confirmed maternity and paternity would be needed to apply PS2.
Sources
PM1 Residue 24 is outside the NRAS RASopathy PM1 domains defined for this specification: P-loop amino acids 10-17 and Switch I amino acids 25-40, as well as SW2 amino acids 57-64 and SAK amino acids 145-156. Therefore this missense change does not meet the domain-based PM1 rule. Details ▾Hide ▴
Rule
PM1 Moderate applies only to specified critical functional domains.
Evidence considered
- PM1 domains for NRAS are limited to amino acids 10-17
- 25-40
- 57-64
- and 145-156.
- p.(Ile24Asn) affects amino acid 24.
Sources
BA1 This variant is absent from gnomAD, which is below the BA1 threshold of at least 0.05% filtering allele frequency. Details ▾Hide ▴
Rule
BA1 requires gnomAD filtering allele frequency at least 0.05%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS1 This variant is absent from gnomAD, which is below the BS1 threshold of at least 0.025% filtering allele frequency. Details ▾Hide ▴
Rule
BS1 requires gnomAD filtering allele frequency at least 0.025%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BP4 BP4 is not met because the REVEL score is 0.863, which is above the benign-supporting threshold of 0.3 or lower for missense variants. Although SpliceAI predicts no splice impact with a maximum delta score of 0.00, the missense predictor result does not support a benign interpretation. Details ▾Hide ▴
Rule
BP4 Supporting for missense variants when REVEL is 0.3 or lower.
Evidence considered
- REVEL 0.863.
- SpliceAI max delta 0.00.
- BayesDel 0.159947.
Sources
Not assessed · 7 · no assessment recorded
PS1 No reviewed evidence was identified showing the same amino acid change established as pathogenic from a different nucleotide change in the permitted NRAS RASopathy framework. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- PS1 is applicable only when the same amino acid change is already established as pathogenic.
Still missing
- Direct confirmation of any alternate-nucleotide pathogenic change producing p.(Ile24Asn) was not identified in the reviewed sources.
Sources
PM5 No reviewed evidence was identified confirming a different pathogenic or likely pathogenic amino acid substitution at this same codon within the permitted RASopathy framework, so PM5 was not applied from the currently reviewed sources. Details ▾Hide ▴
Rule
PM5 Moderate requires one pathogenic or likely pathogenic residue change at the same codon; PM5 Strong requires at least two different such changes in at least 5 probands.
Evidence considered
- PM5 requires a different established pathogenic residue change at the same codon.
Still missing
- Direct codon-level review across the specified RASopathy genes would be needed to confirm whether PM5 can be applied.
Sources
PP1 No segregation data were identified to show that this variant co-segregates with RASopathy across informative meioses. Details ▾Hide ▴
Rule
PP1 requires segregation data with increasing strength by number of informative meioses.
Evidence considered
- No informative segregation evidence was identified in the reviewed materials.
Still missing
- Family-based segregation data would be needed to assess PP1.
Sources
BS2 No evidence was identified showing this variant in unaffected individuals at a level sufficient for BS2 under the NRAS RASopathy point-based framework. Details ▾Hide ▴
Rule
BS2 uses point-based scoring from healthy or apparently unaffected individuals.
Evidence considered
- No unaffected-carrier evidence was identified in the reviewed materials.
Still missing
- Documented unaffected carriers with appropriate phenotypic assessment would be needed to assess BS2.
Sources
BS4 No non-segregation data were identified to show that this variant fails to track with disease in informative relatives. Details ▾Hide ▴
Rule
BS4 requires non-segregation, with one informative meiosis sufficient in this framework.
Evidence considered
- No non-segregation evidence was identified in the reviewed materials.
Still missing
- Family-based non-segregation data would be needed to assess BS4.
Sources
BP2 No evidence was identified showing this variant in cis or trans with an alternative pathogenic molecular explanation sufficient for BP2 point assignment. Details ▾Hide ▴
Rule
BP2 uses point-based scoring for an alternative molecular cause in the same gene and compatible phenotype.
Evidence considered
- No qualifying phase-based alternative-cause evidence was identified.
Still missing
- Phase information and an alternative molecular cause would be needed to assess BP2.
Sources
BP5 No evidence was identified showing an alternative molecular explanation in a different gene or a phenotype fully explained by another cause sufficient for BP5 point assignment. Details ▾Hide ▴
Rule
BP5 uses point-based scoring for an alternate molecular cause in a different gene or a fully explained inconsistent phenotype.
Evidence considered
- No qualifying alternative-cause evidence was identified.
Still missing
- A documented alternative molecular diagnosis or clearly inconsistent phenotype would be needed to assess BP5.
Sources
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense substitution, and the NRAS RASopathy specification marks PVS1 as not applicable for this gene-disease framework. The generic PVS1 scaffold also indicates that this variant is not a null variant eligible for PVS1 assessment. Details ▾Hide ▴
Rule
PVS1 not applicable in the NRAS RASopathy VCEP framework.
Evidence considered
- NRAS RASopathy specification lists PVS1 as not applicable.
- The variant is c.71T>A
- p.(Ile24Asn)
- not a nonsense
- frameshift
- or canonical splice variant.
Sources
PM3 N/APM3 is not applicable in this NRAS RASopathy framework because the relevant disease context is not recessive. Details ▾Hide ▴
Rule
PM3 not applicable.
Evidence considered
- NRAS RASopathy specification lists PM3 as not applicable.
Sources
PM4 N/APM4 is intended for in-frame insertions or deletions and stop-loss variants causing protein length change. This variant is a missense substitution and does not change protein length. Details ▾Hide ▴
Rule
PM4 applies to protein length changes due to in-frame indels or stop-loss variants.
Evidence considered
- c.71T>A causes p.(Ile24Asn)
- a missense substitution.
Sources
PP2 N/APP2 is not applicable in the NRAS RASopathy specification. Details ▾Hide ▴
Rule
PP2 not applicable.
Evidence considered
- NRAS RASopathy specification lists PP2 as not applicable.
Sources
PP4 N/APP4 is not applicable in this NRAS RASopathy framework because phenotype-specific evidence is handled through other criteria such as PS4. Details ▾Hide ▴
Rule
PP4 not applicable.
Evidence considered
- NRAS RASopathy specification lists PP4 as not applicable.
Sources
BS3 N/ABS3 is not applicable in this NRAS RASopathy specification. Details ▾Hide ▴
Rule
BS3 not applicable.
Evidence considered
- NRAS RASopathy specification lists BS3 as not applicable.
Sources
BP1 N/ABP1 in this framework is reserved for truncating loss-of-function variants in a gain-of-function RASopathy gene without an established loss-of-function disease correlation. This variant is a missense substitution, so BP1 does not apply. Details ▾Hide ▴
Rule
BP1 applies to truncating variants in this RASopathy framework.
Evidence considered
- c.71T>A causes a missense change
- p.(Ile24Asn).
Sources
BP3 N/ABP3 is not applicable in this NRAS RASopathy specification. Details ▾Hide ▴
Rule
BP3 not applicable.
Evidence considered
- NRAS RASopathy specification lists BP3 as not applicable.
Sources
BP6 N/ABP6 is not used in this VCEP framework. Details ▾Hide ▴
Rule
BP6 not applicable for this VCEP.
Evidence considered
- NRAS RASopathy specification lists BP6 as not applicable for use.
Sources
BP7 N/ABP7 applies to synonymous or certain non-coding variants with no predicted splice impact. This variant is missense, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous, selected intronic, or non-coding variants.
Evidence considered
- c.71T>A causes p.(Ile24Asn)
- a missense substitution.
- SpliceAI max delta 0.00 does not change the missense nature of the variant.
Sources
Identifiers
- Gene
- NRAS
- Transcript
- NM_002524.4
- Coding (HGVS c.)
- NM_002524.4:c.71T>A
- Protein (HGVS p.)
- NP_002515.1:p.(Ile24Asn)
- GRCh38
- chr1:114716090 A>T
- GRCh37
- chr1:115258711 A>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 SupportingFor this missense variant, the REVEL score is 0.863, which is above the NRAS RASopathy PP3 threshold of 0.7. SpliceAI predicts no splice effect with a maximum delta score of 0.00, supporting interpretation as a missense effect rather than a splicing mechanism. BayesDel is 0.159947 and does not contradict a damaging missense interpretation. Details ▾Hide ▴
Rule
PP3 Supporting for missense variants when REVEL is at least 0.7; for splicing, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.863.
- SpliceAI max delta 0.00.
- BayesDel 0.159947.
Sources
BP4 BP4 is not met because the REVEL score is 0.863, which is above the benign-supporting threshold of 0.3 or lower for missense variants. Although SpliceAI predicts no splice impact with a maximum delta score of 0.00, the missense predictor result does not support a benign interpretation. Details ▾Hide ▴
Rule
BP4 Supporting for missense variants when REVEL is 0.3 or lower.
Evidence considered
- REVEL 0.863.
- SpliceAI max delta 0.00.
- BayesDel 0.159947.
Sources
BP7 N/ABP7 applies to synonymous or certain non-coding variants with no predicted splice impact. This variant is missense, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous, selected intronic, or non-coding variants.
Evidence considered
- c.71T>A causes p.(Ile24Asn)
- a missense substitution.
- SpliceAI max delta 0.00 does not change the missense nature of the variant.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.863. BayesDel score = 0.159947.
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/222971/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-115258711-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-114716090-A-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002524.4%3Ac.71T%…
- OncoKB ↗www.oncokb.org/gene/NRAS/I24N
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NRAS+c.71T%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 Pathogenic (1 clinical laboratory) and as Likely Pathogenic 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 = 0.863. BayesDel score = 0.159947.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
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.