About NRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NRAS c.159G>A, p.(Leu53=)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign 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: 0
Benign evidence criteria: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BA1Stand alone
BA1 · stand alone
Population frequency exceeds the NRAS RASopathy BA1 threshold. In gnomAD v2.1, the highest observed population frequency is 0.12545% in East Asian individuals, which is above the BA1 threshold of 0.05%; gnomAD v4.1 also shows an East Asian frequency of 0.06181%, which is above this threshold.
BS1Strong
BS1 · strong
Population frequency exceeds the NRAS RASopathy BS1 threshold. In gnomAD v2.1, the highest observed population frequency is 0.12545% in East Asian individuals, which is above the BS1 threshold of 0.025%; gnomAD v4.1 also shows an East Asian frequency of 0.06181%, which is above this threshold.
BP6Supporting
BP6 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign.
BP7Supporting
BP7 · supporting
This is a synonymous variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, supporting BP7.
Recorded classification: Benign
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 Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BS1 strong, BP6 supporting benign, BP7 supporting; maps to Benign.
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
27 / 1,522,820 alleles
gnomAD v4.1: 27 / 1,522,820 alleles. Recorded AF 1.77303e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.85545e-05; MAF= 0.00886%, 25/282312 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00125452; MAF= 0.12545%, 25/19928 alleles, homozygotes = 0); grpmax FAF= 0.00090025.
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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: 4 met · 3 not met · 9 not assessed · 12 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.159G>A (p.Leu53=) variant has not been observed in somatic cancers in COSMIC and is reported in ClinVar as Benign by the ClinGen RASopathy Variant Curation Expert Panel.
This variant is present in gnomAD, with the highest observed East Asian allele frequency of 0.12545% in v2.1 and 0.06181% in v4.1, which are above the NRAS RASopathy BA1 threshold of 0.05% and BS1 threshold of 0.025%.
SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.04, supporting no expected RNA effect.
No criteria match.
Met · 4
BA1 Stand alonePopulation frequency exceeds the NRAS RASopathy BA1 threshold. In gnomAD v2.1, the highest observed population frequency is 0.12545% in East Asian individuals, which is above the BA1 threshold of 0.05%; gnomAD v4.1 also shows an East Asian frequency of 0.06181%, which is above this threshold. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.05%.
Evidence considered
- gnomAD v2.1 East Asian AF 0.0012545162585307105 (0.12545%)
- 25/19928 alleles.
- gnomAD v4.1 East Asian AF 0.0006181106418048831 (0.06181%)
- 24/38828 alleles.
- BA1 threshold in NRAS RASopathy specification is filtering allele frequency ≥0.05%.
Sources
BS1 StrongPopulation frequency exceeds the NRAS RASopathy BS1 threshold. In gnomAD v2.1, the highest observed population frequency is 0.12545% in East Asian individuals, which is above the BS1 threshold of 0.025%; gnomAD v4.1 also shows an East Asian frequency of 0.06181%, which is above this threshold. Details ▾Hide ▴
Rule
GnomAD filtering allele frequency ≥0.025%.
Evidence considered
- gnomAD v2.1 East Asian AF 0.0012545162585307105 (0.12545%).
- gnomAD v4.1 East Asian AF 0.0006181106418048831 (0.06181%).
- BS1 threshold in NRAS RASopathy specification is filtering allele frequency ≥0.025%.
Sources
BP6 SupportingExpert panel ClinGen RASopathy Variant Curation Expert Panel classified as Benign. Details ▾Hide ▴
BP7 SupportingThis is a synonymous variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, supporting BP7. Details ▾Hide ▴
Rule
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.
Evidence considered
- Variant consequence is NP_002515.1:p.(Leu53=).
- SpliceAI max delta score is 0.04
- below a level suggesting meaningful splice disruption.
Sources
Not met · 3 · evaluated, threshold not reached
PM1 This variant is at codon 53, which is outside the NRAS PM1 domains defined by the RASopathy specification, and no statistically significant hotspot evidence was identified for this site. Details ▾Hide ▴
Rule
Applicable only to critical and well-established functional domains available in the supplementary table (P-loop 10-17, SW1 25-40, SW2 57-64, SAK 145-156).
Evidence considered
- RASopathy NRAS PM1 domains are P-loop amino acids 10-17
- SW1 amino acids 25-40
- SW2 amino acids 57-64
- and SAK amino acids 145-156.
- Leu53 lies outside those domains.
- Cancer Hotspots did not identify this variant as lying in a statistically significant hotspot.
Sources
PM2 This variant is present in gnomAD and therefore is not absent from controls, so PM2_Supporting is not met. Details ▾Hide ▴
Rule
The variant must be absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1 total AF 0.00886% (25/282312)
- highest East Asian AF 0.12545%.
- gnomAD v4.1 total AF 0.00177% (27/1522820)
- highest East Asian AF 0.06181%.
Sources
PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, and no REVEL, BayesDel, or HCI prior result was available for this synonymous variant. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI DS_AG 0.02
- DS_AL 0.04
- DS_DG 0.00
- DS_DL 0.01
- max delta 0.04.
- No REVEL
- BayesDel
- or HCI prior score was available.
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo occurrence with sufficient parental confirmation and phenotype detail was identified for this variant, so PS2 cannot be assigned from the available evidence. Details ▾Hide ▴
Rule
Follow SVI recommendations for point-based scoring in conjunction with PM6 and RASopathy phenotypic specifications.
Evidence considered
- ClinVar summary identifies benign and likely benign submissions but no confirmed de novo evidence for this variant.
- NRAS RASopathy PS2 requires point-based de novo evidence.
Still missing
- Confirmed maternity and paternity testing were not identified.
- Phenotype-specific point scoring information was not identified.
Sources
PS3 No variant-specific approved functional study was identified for this synonymous variant, so PS3 cannot be applied. Details ▾Hide ▴
Rule
PS3 Moderate requires two or more different approved assays; PS3 Supporting requires one approved assay.
Evidence considered
- The NRAS VCEP functional studies resource lists approved assay types for RASopathy interpretation.
- No entry matching L53=
- Leu53=
- or c.159G>A was identified in the approved functional studies file.
Still missing
- No published approved assay result for NM_002524.4:c.159G>A was identified.
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PS4 No affected-proband count or case enrichment data were identified for this exact variant, so PS4 cannot be scored. Details ▾Hide ▴
Rule
PS4 uses the RASopathy VCEP point-based framework for affected individuals.
Evidence considered
- ClinVar reports this variant as benign/likely benign
- including expert-panel review.
- Population data show the variant is present in gnomAD
- which does not support rarity-based case enrichment.
Still missing
- No case series or point-based affected-individual data were identified for this variant.
Sources
PM6 No presumed de novo report without full parental confirmation was identified for this variant, so PM6 cannot be assigned. Details ▾Hide ▴
Rule
PM6 uses point-based scoring for assumed de novo occurrences.
Evidence considered
- ClinVar summary does not provide PM6-type de novo evidence for this variant.
- NRAS RASopathy PM6 requires point-based de novo evidence.
Still missing
- No de novo case report with incomplete parentage confirmation was identified.
Sources
PP1 No segregation data were identified for this variant, so PP1 cannot be applied. Details ▾Hide ▴
BS2 No healthy adult carrier observations meeting the RASopathy point-based BS2 framework were identified for this variant. Details ▾Hide ▴
Rule
BS2 uses point-based scoring based on healthy or apparently unaffected individuals.
Evidence considered
- BS2 in the NRAS RASopathy framework requires point-based unaffected-individual evidence.
Still missing
- No phenotyped unaffected carrier data were identified.
Sources
BS4 No nonsegregation data were identified for this variant, so BS4 cannot be applied. Details ▾Hide ▴
BP2 No data were identified showing this variant in cis or trans with another pathogenic RASopathy variant or establishing an alternative molecular explanation under the RASopathy point-based framework. Details ▾Hide ▴
Rule
Points are awarded for an alternative molecular cause or phase-based evidence under the RASopathy framework.
Evidence considered
- BP2 in the NRAS RASopathy framework requires point-based molecular evidence.
Still missing
- No phase data with another pathogenic variant were identified.
- No alternative molecular diagnosis data were identified.
Sources
BP5 No evidence was identified for another molecular finding that would better explain the phenotype, so BP5 cannot be assigned. Details ▾Hide ▴
Rule
BP5 uses point-based scoring for an alternate molecular explanation of the phenotype.
Evidence considered
- BP5 in the NRAS RASopathy framework requires point-based alternative-cause evidence.
Still missing
- No alternative molecular diagnosis data were identified.
Sources
Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPThe NRAS RASopathy specification marks PVS1 as not applicable for this variant, and this synonymous change is not a nonsense, frameshift, or canonical splice-site variant. Details ▾Hide ▴
VCEP rule
RASopathy NRAS VCEP: PVS1 not applicable.
Evidence considered
- NRAS VCEP/CSPEC lists PVS1 as not applicable.
- NM_002524.4:c.159G>A is a synonymous variant
- NP_002515.1:p.(Leu53=)
- outside the default generic null-variant buckets.
Sources
PS1 N/AThis criterion is intended for an established pathogenic amino acid substitution, but this variant does not change the amino acid sequence. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- Protein consequence is NP_002515.1:p.(Leu53=).
- NRAS PS1 rule is framed around the same amino acid change as a previously established pathogenic variant.
Sources
PM3 VCEPPM3 is not applicable under the NRAS RASopathy specification. Details ▾Hide ▴
PM4 N/AThis synonymous substitution does not change protein length or alter the reading frame, so PM4 does not apply. Details ▾Hide ▴
Rule
PM4 applies to protein length changes in a non-repeat region.
Evidence considered
- Protein consequence is p.(Leu53=)
- with no in-frame insertion/deletion or stop-loss effect.
Sources
PM5 N/AThe NRAS PM5 rule is classic same-residue missense logic, but this variant is synonymous rather than missense. Details ▾Hide ▴
Rule
PM5 applies to missense variation at the same codon as a pathogenic or likely pathogenic missense change.
Evidence considered
- PM5 candidate review determined the variant is not eligible for classic same-residue missense PM5 search.
- Protein consequence is p.(Leu53=).
Sources
cspec ↗pm5_candidates
PP2 VCEPPP2 is not applicable under the NRAS RASopathy specification. Details ▾Hide ▴
PP4 VCEPPP4 is not applicable under the NRAS RASopathy specification. Details ▾Hide ▴
PP5 VCEPPP5 is not applicable under the NRAS RASopathy specification. Details ▾Hide ▴
BS3 VCEPBS3 is not applicable under the NRAS RASopathy specification. Details ▾Hide ▴
BP1 N/AThe NRAS RASopathy BP1 rule is intended for truncating or other loss-of-function variants in a gain-of-function disease setting, and this variant is a synonymous substitution. Details ▾Hide ▴
Rule
Use for truncating LOF variants in genes for which primarily missense GOF variants are known to cause disease.
Evidence considered
- Protein consequence is p.(Leu53=)
- not a truncating or canonical splice variant.
Sources
BP3 VCEPBP3 is not applicable under the NRAS RASopathy specification. Details ▾Hide ▴
BP4 N/AThe NRAS RASopathy BP4 rule is specified for missense variants with REVEL 0.3 or lower, but this variant is synonymous rather than missense. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
- Protein consequence is p.(Leu53=).
- NRAS BP4 rule is defined for missense variants.
Sources
Identifiers
- Gene
- NRAS
- Transcript
- NM_002524.4
- Coding (HGVS c.)
- NM_002524.4:c.159G>A
- Protein (HGVS p.)
- NP_002515.1:p.(Leu53=)
- GRCh38
- chr1:114713931 C>T
- GRCh37
- chr1:115256552 C>T
- ClinVar
- 164807
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
27 / 1,522,820 alleles
AF 1.77e-05 · 0 homozygotes · FAF 0.000426
gnomAD v2.1
25 / 282,312 alleles
AF 8.86e-05 · 0 homozygotes · FAF 0.0009
By genetic ancestry
gnomAD v4.1
AF 1.8e-05 · 27 / 1,522,820 alleles · 0 hom · FAF 0.00043
| East Asian24 / 38,828 | 0.00062 |
| Remaining individuals2 / 56,734 | 3.5e-05 |
| European (non-Finnish)1 / 1,122,562 | 8.9e-07 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 8.9e-05 · 25 / 282,312 alleles · 0 hom · FAF 0.0009
| East Asian25 / 19,928 | 0.0013 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.77303e-05; MAF= 0.00177%, 27/1522820 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000618111; MAF= 0.06181%, 24/38828 alleles, homozygotes = 0); grpmax FAF= 0.0004261.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.85545e-05; MAF= 0.00886%, 25/282312 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00125452; MAF= 0.12545%, 25/19928 alleles, homozygotes = 0); grpmax FAF= 0.00090025.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP7 SupportingThis is a synonymous variant, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, supporting BP7. Details ▾Hide ▴
Rule
A synonymous variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site.
Evidence considered
- Variant consequence is NP_002515.1:p.(Leu53=).
- SpliceAI max delta score is 0.04
- below a level suggesting meaningful splice disruption.
Sources
PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.04, and no REVEL, BayesDel, or HCI prior result was available for this synonymous variant. Details ▾Hide ▴
Rule
For missense variants: REVEL ≥0.7. For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI DS_AG 0.02
- DS_AL 0.04
- DS_DG 0.00
- DS_DL 0.01
- max delta 0.04.
- No REVEL
- BayesDel
- or HCI prior score was available.
Sources
BP4 N/AThe NRAS RASopathy BP4 rule is specified for missense variants with REVEL 0.3 or lower, but this variant is synonymous rather than missense. Details ▾Hide ▴
Rule
For missense variants: REVEL ≤0.3.
Evidence considered
- Protein consequence is p.(Leu53=).
- NRAS BP4 rule is defined for missense variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 24033266 ↗A systematic approach to assessing the clinical significance of genetic variants.Duzkale H et al. · 2013No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
27 / 1,522,820 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
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/164807/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-115256552-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-114713931-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002524.4%3Ac.159G…
- OncoKB ↗www.oncokb.org/gene/NRAS/L53=
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NRAS+c.159G%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
This variant is present in gnomAD v4.1 (AF= 1.77303e-05; MAF= 0.00177%, 27/1522820 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000618111; MAF= 0.06181%, 24/38828 alleles, homozygotes = 0); grpmax FAF= 0.0004261.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.85545e-05; MAF= 0.00886%, 25/282312 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.00125452; MAF= 0.12545%, 25/19928 alleles, homozygotes = 0); grpmax FAF= 0.00090025.
ClinVar
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Benign (3 clinical laboratories) and as Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 164807)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).
Functional
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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.