About NRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NRAS c.173C>T, p.(Thr58Ile)
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: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Moderate
PS3 · moderate
In the RASopathy VCEP-approved functional studies resource, NRAS p.Thr58Ile is listed among pathogenic or likely pathogenic validation controls in multiple approved assay classes, including RAS activation, MEK activation, and ERK activation assays. These data support an abnormal functional effect consistent with pathogenic activation.
PM1Moderate
PM1 · moderate
The p.Thr58Ile change lies in the NRAS Switch II region (amino acids 57-64), which the NRAS RASopathy VCEP designates as a critical and well-established functional domain for PM1.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the NRAS RASopathy VCEP PM2 requirement that the variant be absent from controls.
PP3Supporting
PP3 · supporting
For this missense variant, the REVEL score is 0.959, which is above the NRAS RASopathy VCEP PP3 threshold of 0.7. BayesDel is also positive at 0.45829, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, supporting a missense rather than splice-driven damaging effect.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.
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: PS3 moderate, PM1 moderate, PM2 supporting, PP3 supporting, PP5 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.
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: 5 met · 5 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 NM_002524.4:c.173C>T (NP_002515.1:p.Thr58Ile; NP_002515.1:p.T58I) variant has been observed in somatic cancers in COSMIC (COSV54738937, n=4) and has been reported in ClinVar as pathogenic, including expert panel review by the ClinGen RASopathy Variant Curation Expert Panel.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population databases.
In the RASopathy VCEP-approved functional studies resource, NRAS p.Thr58Ile is listed as a pathogenic or likely pathogenic validation control across multiple approved assay classes, including RAS activation, MEK activation, and ERK activation assays, supporting an abnormal activating effect.
Computational evidence supports a damaging missense effect, with REVEL 0.959 and BayesDel 0.45829, while SpliceAI predicts no significant splice impact (maximum delta score 0.01).
No criteria match.
Met · 5
PS3 ModerateIn the RASopathy VCEP-approved functional studies resource, NRAS p.Thr58Ile is listed among pathogenic or likely pathogenic validation controls in multiple approved assay classes, including RAS activation, MEK activation, and ERK activation assays. These data support an abnormal functional effect consistent with pathogenic activation. Details ▾Hide ▴
Rule
Two or more different approved assays.
Evidence considered
- NRAS p.T58I appears as a pathogenic/likely pathogenic validation control in approved RAS activation
- MEK activation
- and ERK activation assays.
Sources
vcep_svi_rasopathy_vcep_v2_approved_functional_studiescspec ↗
PM1 ModerateThe p.Thr58Ile change lies in the NRAS Switch II region (amino acids 57-64), which the NRAS RASopathy VCEP designates as a critical and well-established functional domain for PM1. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional domains; SW2 amino acids 57-64.
Evidence considered
- Thr58 falls within the VCEP-defined SW2 domain spanning amino acids 57-64.
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, which meets the NRAS RASopathy VCEP PM2 requirement that the variant be absent from controls. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
PP3 SupportingFor this missense variant, the REVEL score is 0.959, which is above the NRAS RASopathy VCEP PP3 threshold of 0.7. BayesDel is also positive at 0.45829, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, supporting a missense rather than splice-driven damaging effect. Details ▾Hide ▴
Rule
For missense variants: REVEL >= 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL score 0.959.
- BayesDel score 0.45829.
- SpliceAI max delta score 0.01.
Sources
Not met · 5 · evaluated, threshold not reached
PS1 No previously established pathogenic variant causing the same amino acid change from a different nucleotide change was identified in the available evidence. Details ▾Hide ▴
PM5 No different pathogenic or likely pathogenic missense change at the same codon was identified in the available evidence to support PM5. Details ▾Hide ▴
BA1 This variant is absent from gnomAD and therefore is below the BA1 stand-alone benign threshold of 0.05%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BS1 This variant is absent from gnomAD and therefore is below the BS1 strong benign threshold of 0.025%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
BP4 Computational evidence does not support a benign interpretation. The REVEL score is 0.959, which is above the BP4 benign threshold of 0.3, and BayesDel is also positive at 0.45829. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, but that does not outweigh the damaging missense predictions. Details ▾Hide ▴
Evidence considered
- REVEL score 0.959.
- BayesDel score 0.45829.
- SpliceAI max delta score 0.01.
Sources
Not assessed · 8 · no assessment recorded
PS2 This variant has been reported in germline disease databases, but no confirmed de novo occurrence with both maternity and paternity established was identified in the available evidence. Details ▾Hide ▴
PS4 This variant has been observed in affected submissions in ClinVar, but the available evidence does not provide the proband counts or point-based case evidence needed for PS4 under the NRAS RASopathy VCEP framework. Details ▾Hide ▴
PM6 No assumed de novo occurrence without confirmed maternity and paternity was documented in the available evidence, so PM6 was not applied. Details ▾Hide ▴
PP1 No segregation data were identified to support or refute cosegregation with disease. Details ▾Hide ▴
BS2 No observations in clearly unaffected individuals were identified to support BS2. Details ▾Hide ▴
Still missing
- Documented unaffected carriers scored under the VCEP point system would be needed.
Sources
BS4 No nonsegregation data were identified to support BS4. Details ▾Hide ▴
Still missing
- At least one informative meiosis showing nonsegregation would be needed.
Sources
BP2 No evidence was identified that this variant was observed with an alternative molecular explanation meeting the VCEP BP2 point-based framework. Details ▾Hide ▴
Still missing
- Phase information and an alternative disease-causing variant would be needed.
Sources
BP5 No alternative molecular cause explaining the phenotype was identified to support BP5. Details ▾Hide ▴
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the NRAS RASopathy VCEP framework lists PVS1 as not applicable. The generic PVS1 scaffold also does not apply because this variant is not a nonsense, frameshift, or canonical +/-1,2 splice variant. Details ▾Hide ▴
Evidence considered
- NRAS RASopathy VCEP lists PVS1 as not applicable.
- Generic PVS1 assessment does not place p.Thr58Ile in a null-variant category.
Sources
PM3 N/APM3 is not applicable in the NRAS RASopathy VCEP framework. Details ▾Hide ▴
PM4 N/AThis variant is a missense substitution and does not cause a protein length change, in-frame deletion, or in-frame insertion, so PM4 does not apply. Details ▾Hide ▴
PP2 N/APP2 is not applicable in the NRAS RASopathy VCEP framework. Details ▾Hide ▴
PP4 N/APP4 is not applicable in the NRAS RASopathy VCEP framework. Details ▾Hide ▴
BS3 N/ABS3 is not applicable in the NRAS RASopathy VCEP framework for this evidence set, and no validated benign functional evidence was identified. Details ▾Hide ▴
BP1 N/ABP1 in this framework is intended for truncating or loss-of-function variants in a gain-of-function RASopathy gene. This variant is missense, so BP1 does not apply. Details ▾Hide ▴
BP3 N/ABP3 is not applicable in the NRAS RASopathy VCEP framework. Details ▾Hide ▴
BP6 N/ABP6 is not applicable in the NRAS RASopathy VCEP framework. Details ▾Hide ▴
BP7 N/AThis variant is missense rather than synonymous or intronic, so BP7 does not apply. Details ▾Hide ▴
Identifiers
- Gene
- NRAS
- Transcript
- NM_002524.4
- Coding (HGVS c.)
- NM_002524.4:c.173C>T
- Protein (HGVS p.)
- NP_002515.1:p.(Thr58Ile)
- GRCh38
- chr1:114713917 G>A
- GRCh37
- chr1:115256538 G>A
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 0.959, which is above the NRAS RASopathy VCEP PP3 threshold of 0.7. BayesDel is also positive at 0.45829, while SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, supporting a missense rather than splice-driven damaging effect. Details ▾Hide ▴
Rule
For missense variants: REVEL >= 0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- REVEL score 0.959.
- BayesDel score 0.45829.
- SpliceAI max delta score 0.01.
Sources
BP4 Computational evidence does not support a benign interpretation. The REVEL score is 0.959, which is above the BP4 benign threshold of 0.3, and BayesDel is also positive at 0.45829. SpliceAI predicts no meaningful splice effect with a maximum delta score of 0.01, but that does not outweigh the damaging missense predictions. Details ▾Hide ▴
Evidence considered
- REVEL score 0.959.
- BayesDel score 0.45829.
- SpliceAI max delta score 0.01.
Sources
BP7 N/AThis variant is missense rather than synonymous or intronic, so BP7 does not apply. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.959. BayesDel score = 0.45829.
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/1070042/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-115256538-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-114713917-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002524.4%3Ac.173C…
- OncoKB ↗www.oncokb.org/gene/NRAS/T58I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=116672884
- 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 (3 clinical laboratories) and as Likely pathogenic (2 clinical laboratories) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.959. BayesDel score = 0.45829.
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 previously been reported in somatic cancers (COSMIC; COSV54738937, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.