About NRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NRAS c.112-8A>G, p.?
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely 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: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BS1Strong
BS1 · strong
BS1 requires a gnomAD filtering allele frequency of at least 0.025%. The observed grpmax FAF is 0.03711% in gnomAD v2.1 and 0.04727% in gnomAD v4.1, both above the 0.025% threshold, so BS1 is met at strong strength.
BP6Supporting
BP6 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely benign.
Recorded classification: Likely 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 Rule20 (1 Benign.Strong) with applied criteria: BS1 strong, BP6 supporting benign; maps to Likely 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
529 / 1,340,490 alleles
gnomAD v4.1: 529 / 1,340,490 alleles. Recorded AF 0.000394632. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000255817; MAF= 0.02558%, 71/277542 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000487061; MAF= 0.04871%, 62/127294 alleles, homozygotes = 0); grpmax FAF= 0.00037107.
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.
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Context only
COSMIC ↗
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 · 4 not met · 9 not assessed · 13 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.112-8A>G (p.?) variant has been reported in ClinVar, where the aggregate classification is likely benign and expert panel review is present.
This variant is present in population databases, with gnomAD v2.1 total AF 0.02558% and grpmax FAF 0.03711%, and gnomAD v4.1 total AF 0.03946% and grpmax FAF 0.04727%, which is above the NRAS RASopathy BS1 threshold of 0.025% but below the BA1 threshold of 0.05%.
SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.02, which does not support a deleterious splicing prediction.
No criteria match.
Met · 2
BS1 StrongBS1 requires a gnomAD filtering allele frequency of at least 0.025%. The observed grpmax FAF is 0.03711% in gnomAD v2.1 and 0.04727% in gnomAD v4.1, both above the 0.025% threshold, so BS1 is met at strong strength. Details ▾Hide ▴
Rule
BS1 Strong: gnomAD filtering allele frequency >=0.025%.
Evidence considered
- gnomAD v2.1 grpmax FAF exceeds 0.025%
- gnomAD v4.1 grpmax FAF exceeds 0.025%
Sources
Not met · 4 · evaluated, threshold not reached
PS4 This variant is present in population databases and no affected-case enrichment data were identified. Available evidence does not show the case-count excess required for PS4. Details ▾Hide ▴
Rule
RASopathy VCEP point-based case enrichment scoring for PS4.
Evidence considered
- Variant observed repeatedly in gnomAD
- No case-enrichment dataset or point total was retrieved
Still missing
- Defined affected-case counts or point-based case evidence under the RASopathy specification
Sources
PM2 PM2_Supporting requires absence from gnomAD. This variant is present in gnomAD v2.1 at AF 0.02558% (71/277542) and in gnomAD v4.1 at AF 0.03946% (529/1340490), so the absence threshold is not met. Details ▾Hide ▴
Rule
PM2 Supporting: variant must be absent from controls (gnomAD).
Evidence considered
- gnomAD v2.1 total AF 0.000255817
- gnomAD v4.1 total AF 0.000394632
Sources
PP3 For splice prediction, PP3 requires a predicted splicing outcome that matches the disease mechanism. SpliceAI shows a maximum delta score of 0.02, which predicts no significant splice impact. REVEL and BayesDel are not available for this intronic variant. Available computational evidence therefore does not support PP3. Details ▾Hide ▴
Rule
For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI max delta score 0.02 with no significant predicted splice effect
- No REVEL or BayesDel score available
Sources
BA1 BA1 requires a gnomAD filtering allele frequency of at least 0.05%. The observed grpmax FAF is 0.03711% in gnomAD v2.1 and 0.04727% in gnomAD v4.1, both below the 0.05% threshold, so BA1 is not met. Details ▾Hide ▴
Rule
BA1: gnomAD filtering allele frequency >=0.05%.
Evidence considered
- gnomAD v2.1 grpmax FAF 0.00037107
- gnomAD v4.1 grpmax FAF 0.00047274
Sources
Not assessed · 9 · no assessment recorded
PS2 No confirmed de novo occurrence with maternity and paternity established was identified. Available evidence does not provide the case-level trio data required for PS2 point assignment. Details ▾Hide ▴
Rule
Point-based de novo scoring under the RASopathy specification.
Evidence considered
- No de novo details were retrieved from the reviewed ClinVar summary
- RASopathy VCEP uses point-based de novo scoring
Still missing
- Confirmed maternity and paternity for an affected individual with this variant
- Phenotype details sufficient for RASopathy point assignment
Sources
PS3 No approved functional or RNA assay result for this specific splice-region variant was identified. Available evidence therefore does not support applying PS3. Details ▾Hide ▴
Rule
PS3 Supporting requires one approved assay; PS3 Moderate requires two or more different approved assays.
Evidence considered
- RASopathy VCEP requires one or more approved assays
- No exact-variant functional study was retrieved
Still missing
- Direct RNA study
- minigene assay
- or other approved functional assay for this variant
Sources
cspec ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
PM6 No assumed de novo report for this variant was identified. Available evidence does not provide the case-level inheritance information required for PM6 point assignment. Details ▾Hide ▴
Rule
Point-based assumed de novo scoring under the RASopathy specification.
Evidence considered
- No de novo submission detail was retrieved
- RASopathy VCEP uses point-based scoring for PM6
Still missing
- Affected individual with this variant and de novo evidence lacking full parental confirmation
Sources
PP1 No segregation data were identified for this variant. Available evidence does not provide informative meioses to support PP1. Details ▾Hide ▴
BS2 Although this variant is present in population databases, no phenotype-qualified healthy adult observations or point-based evidence meeting the RASopathy BS2 specification were identified. Available evidence is insufficient to apply BS2. Details ▾Hide ▴
Rule
BS2 uses point-based healthy observation scoring with phenotypic specifications.
Evidence considered
- Population frequency data alone do not establish BS2 under the VCEP point framework
Still missing
- Case-level or cohort-level healthy adult observations that satisfy RASopathy BS2 point criteria
Sources
BS4 No nonsegregation data were identified for this variant. Available evidence does not support BS4. Details ▾Hide ▴
Rule
BS4 requires nonsegregation data.
Evidence considered
- No family-based nonsegregation evidence was retrieved
Still missing
- Family data showing lack of segregation with phenotype
Sources
BP2 No evidence was identified that this variant occurs in cis or trans with another established pathogenic RASopathy variant or that the required point-based alternative-molecular-cause framework is satisfied. BP2 cannot be applied from the available evidence. Details ▾Hide ▴
Rule
BP2 uses point-based scoring for alternative molecular causes in the RASopathy specification.
Evidence considered
- No phasing or alternative same-gene molecular explanation was retrieved
Still missing
- Phasing data with another pathogenic variant and phenotype context
Sources
BP5 No alternative molecular explanation for the phenotype in another gene, and no phenotype-based evidence against this variant, were identified. Available evidence is insufficient to apply BP5. Details ▾Hide ▴
Rule
BP5 uses point-based alternative-diagnosis or phenotype-inconsistency evidence.
Evidence considered
- No alternative molecular diagnosis was retrieved
Still missing
- Documented alternative molecular diagnosis or phenotype inconsistency meeting RASopathy BP5 point criteria
Sources
BP7 This noncanonical intronic variant has a low SpliceAI maximum delta score of 0.02, which predicts no significant splice impact. However, the BP7 specification also requires that the nucleotide not be highly conserved, and no conservation evidence was identified, so BP7 is not applied. Details ▾Hide ▴
Rule
BP7 requires no predicted splice impact and lack of high conservation.
Evidence considered
- SpliceAI max delta score 0.02
- No conservation data retrieved
Still missing
- Conservation evidence for the altered intronic nucleotide
Sources
Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis intronic variant is at c.112-8 and does not affect a canonical +/-1 or +/-2 splice site. The NRAS RASopathy specification marks PVS1 as not applicable for this gene framework, and the generic PVS1 scaffold does not place this variant in a default null-variant category. Details ▾Hide ▴
Rule
PVS1 not applicable in the NRAS RASopathy VCEP framework.
Evidence considered
- NRAS RASopathy specification lists PVS1 as not applicable
- Variant is noncanonical intronic (-8) rather than a canonical splice-site or other default null variant
Sources
PS1 N/AThis criterion is for the same amino acid change as a previously established pathogenic variant. This variant is intronic with no defined amino acid substitution, so PS1 is not applicable. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant.
Evidence considered
- Protein consequence is p.?
- PS1 in this framework applies to amino acid changes
Sources
PM1 N/APM1 in the NRAS RASopathy specification applies to established protein functional domains such as the P-loop, SW1, SW2, and SAK. This variant is an intronic splice-region change and does not map to a protein residue within those domains. Details ▾Hide ▴
Rule
Applicable only to specified protein functional domains; not applicable to noncoding intronic positions.
Evidence considered
- PM1 domains are protein regions
- Variant is intronic c.112-8A>G with protein consequence p.?
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
PM3 N/APM3 is not applicable in the NRAS RASopathy specification. Details ▾Hide ▴
Rule
Not applicable in this VCEP framework.
Evidence considered
- RASopathy VCEP marks PM3 as not applicable
Sources
PM4 N/APM4 applies to in-frame insertions or deletions and stop-loss variants. This variant is a noncoding intronic substitution, so PM4 is not applicable. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions or stop-loss variants.
Evidence considered
- Variant is an intronic single-nucleotide substitution
Sources
PM5 N/APM5 is for a novel missense change at a residue where a different pathogenic missense change has been seen. This variant is intronic with no codon substitution, so PM5 is not applicable. Details ▾Hide ▴
Rule
Observed pathogenic missense change at the same codon.
Evidence considered
- Protein consequence is p.?
- PM5 applies to missense residue substitutions
Sources
PP2 N/APP2 is not applicable in the NRAS RASopathy specification. Details ▾Hide ▴
Rule
Not applicable in this VCEP framework.
Evidence considered
- RASopathy VCEP marks PP2 as not applicable
Sources
PP4 N/APP4 is not applicable in the NRAS RASopathy specification. Details ▾Hide ▴
Rule
Not applicable in this VCEP framework.
Evidence considered
- RASopathy VCEP marks PP4 as not applicable
Sources
PP5 N/APP5 is not for use in this VCEP framework. Details ▾Hide ▴
Rule
Not applicable in this VCEP framework.
Evidence considered
- RASopathy VCEP marks PP5 as not applicable
Sources
BS3 N/ABS3 is not applicable in the NRAS RASopathy specification. Details ▾Hide ▴
Rule
Not applicable in this VCEP framework.
Evidence considered
- RASopathy VCEP marks BS3 as not applicable
Sources
BP1 N/AIn this framework, BP1 is used for truncating or canonical splice variants in a gene where gain-of-function missense variants cause disease. This variant is a noncanonical intronic change at c.112-8, so BP1 is not applicable. Details ▾Hide ▴
Rule
BP1 applies to truncating or canonical splice variants in this RASopathy specification.
Evidence considered
- Variant is not truncating and does not affect a canonical splice site
Sources
BP3 N/ABP3 is not applicable in the NRAS RASopathy specification. Details ▾Hide ▴
Rule
Not applicable in this VCEP framework.
Evidence considered
- RASopathy VCEP marks BP3 as not applicable
Sources
BP4 N/AIn this framework, BP4 is defined for missense variants with REVEL <=0.3. This variant is intronic rather than missense, and no REVEL or BayesDel score is available, so BP4 is not applicable. Details ▾Hide ▴
Rule
BP4 Supporting: for missense variants, REVEL <=0.3.
Evidence considered
- Variant is intronic
- not missense
- No REVEL or BayesDel score available
Sources
Identifiers
- Gene
- NRAS
- Transcript
- NM_002524.4
- Coding (HGVS c.)
- NM_002524.4:c.112-8A>G
- Protein (HGVS p.)
- NP_002515.1:p.?
- GRCh38
- chr1:114713986 T>C
- GRCh37
- chr1:115256607 T>C
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
529 / 1,340,490 alleles
AF 0.000395 · 0 homozygotes · FAF 0.000473
gnomAD v2.1
71 / 277,542 alleles
AF 0.000256 · 0 homozygotes · FAF 0.000371
By genetic ancestry
gnomAD v4.1
AF 0.00039 · 529 / 1,340,490 alleles · 0 hom · FAF 0.00047
| European (non-Finnish)499 / 977,102 | 0.00051 |
| European (Finnish)12 / 48,214 | 0.00025 |
| Remaining individuals12 / 48,538 | 0.00025 |
| African/African American6 / 66,904 | 9e-05 |
0 alternate alleles recorded in 6 other groups: Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00026 · 71 / 277,542 alleles · 0 hom · FAF 0.00037
| European (non-Finnish)62 / 127,294 | 0.00049 |
| European (Finnish)5 / 24,796 | 0.0002 |
| Remaining individuals1 / 7,036 | 0.00014 |
| African/African American3 / 24,648 | 0.00012 |
0 alternate alleles recorded in 4 other groups: Admixed American, Ashkenazi Jewish, East Asian, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000394632; MAF= 0.03946%, 529/1340490 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000510694; MAF= 0.05107%, 499/977102 alleles, homozygotes = 0); grpmax FAF= 0.00047274.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000255817; MAF= 0.02558%, 71/277542 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000487061; MAF= 0.04871%, 62/127294 alleles, homozygotes = 0); grpmax FAF= 0.00037107.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 For splice prediction, PP3 requires a predicted splicing outcome that matches the disease mechanism. SpliceAI shows a maximum delta score of 0.02, which predicts no significant splice impact. REVEL and BayesDel are not available for this intronic variant. Available computational evidence therefore does not support PP3. Details ▾Hide ▴
Rule
For splicing impact, predicted outcome must match disease mechanism.
Evidence considered
- SpliceAI max delta score 0.02 with no significant predicted splice effect
- No REVEL or BayesDel score available
Sources
BP7 This noncanonical intronic variant has a low SpliceAI maximum delta score of 0.02, which predicts no significant splice impact. However, the BP7 specification also requires that the nucleotide not be highly conserved, and no conservation evidence was identified, so BP7 is not applied. Details ▾Hide ▴
Rule
BP7 requires no predicted splice impact and lack of high conservation.
Evidence considered
- SpliceAI max delta score 0.02
- No conservation data retrieved
Still missing
- Conservation evidence for the altered intronic nucleotide
Sources
BP4 N/AIn this framework, BP4 is defined for missense variants with REVEL <=0.3. This variant is intronic rather than missense, and no REVEL or BayesDel score is available, so BP4 is not applicable. Details ▾Hide ▴
Rule
BP4 Supporting: for missense variants, REVEL <=0.3.
Evidence considered
- Variant is intronic
- not missense
- No REVEL or BayesDel score available
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
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
529 / 1,340,490 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 ↗
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/138538/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-115256607-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-114713986-T-C?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002524.4%3Ac.112-…
- OncoKB ↗www.oncokb.org/gene/NRAS/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NRAS+c.112-8A%3EG
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= 0.000394632; MAF= 0.03946%, 529/1340490 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000510694; MAF= 0.05107%, 499/977102 alleles, homozygotes = 0); grpmax FAF= 0.00047274.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000255817; MAF= 0.02558%, 71/277542 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000487061; MAF= 0.04871%, 62/127294 alleles, homozygotes = 0); grpmax FAF= 0.00037107.
ClinVar
This variant has been reported in ClinVar as Likely benign (4 clinical laboratories) and as Benign (2 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Uncertain significance (1 clinical laboratory) and as Likely Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).