About NRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NRAS c.291-8G>A, p.?
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: 0
Benign evidence criteria: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BP4Supporting
BP4 · supporting
SpliceAI predicts no splicing impact (max delta score = 0.01). The predicted splicing outcome is negligible and does not support a gain-of-function disease mechanism for RASopathies. Per VCEP BP4 instructions, this criterion is applicable for splicing variants where the predicted outcome is negligible or does not match the disease mechanism.
BP6Supporting
BP6 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely benign.
BP7Supporting
BP7 · supporting
c.291-8G>A is an intronic variant at position -8 from exon 3 (not a canonical splice site). SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site (max delta = 0.01). Per VCEP BP7, this rule is applicable for intronic positions except canonical splice sites and should be used in conjunction with BP4.
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: BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; 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
167 / 1,607,416 alleles
gnomAD v4.1: 167 / 1,607,416 alleles. Recorded AF 0.000103893. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.36528e-05; MAF= 0.00637%, 18/282784 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138466; MAF= 0.01385%, 1/7222 alleles, homozygotes = 0); grpmax FAF= 4.736e-05.
No listed criterion applied
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
3 Likely benign · 1 Uncertain significance · 1 Benign.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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.
26 criteria with recorded statuses: 3 met · 13 not met · 0 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
NM_002524.4:c.291-8G>A is an intronic variant in NRAS (intron 2, c.291-8).
The ClinGen RASopathy Expert Panel VCEP v2.3.0 was applied as the primary classification framework.
No pathogenic criteria were met. PVS1, PS1, PS5, PM1, PM5, PP2, PP4, PP5, BS3, BP1, BP3, BP6, PM3, and PM4 are not applicable to this intronic variant per VCEP specifications.
Two benign supporting criteria are met: BP4 (SpliceAI predicts no splicing impact; max delta 0.01; predicted outcome does not match gain-of-function disease mechanism) and BP7 (intronic variant at non-canonical position with no predicted splice effect).
The variant is present in gnomAD at low frequency: v2.1 AF=0.0064% (18/282,784 alleles), v4.1 AF=0.010% (167/1,607,416 alleles, 1 homozygote). These frequencies do not reach VCEP thresholds for BA1 (>=0.05%) or BS1 (>=0.025%), but the presence in population databases precludes PM2 (which requires absence from gnomAD).
No de novo occurrences, functional studies, cosegregation data, or case-control enrichment have been reported for this variant in ClinVar or the published literature.
Per VCEP Rule 19, >=2 supporting benign criteria (BP4 + BP7) classifies this variant as Likely Benign.
This classification is concordant with the ClinGen RASopathy VCEP expert panel assessment of Likely Benign (ClinVar Variation ID 44575).
No criteria match.
Met · 3
BP4 SupportingSpliceAI predicts no splicing impact (max delta score = 0.01). The predicted splicing outcome is negligible and does not support a gain-of-function disease mechanism for RASopathies. Per VCEP BP4 instructions, this criterion is applicable for splicing variants where the predicted outcome is negligible or does not match the disease mechanism. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01
- predicting no splice-altering effect
- REVEL not applicable for intronic variant
- multiple computational lines (SpliceAI) consistently predict no impact.
Sources
BP6 SupportingExpert panel ClinGen RASopathy Variant Curation Expert Panel classified as Likely benign. Details ▾Hide ▴
BP7 Supportingc.291-8G>A is an intronic variant at position -8 from exon 3 (not a canonical splice site). SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site (max delta = 0.01). Per VCEP BP7, this rule is applicable for intronic positions except canonical splice sites and should be used in conjunction with BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01
- no predicted donor/acceptor gain or loss
- variant is at intronic position -8
- not at a canonical +/-1
- 2 splice site.
Sources
Not met · 13 · evaluated, threshold not reached
PS2 No de novo occurrence with confirmed maternity and paternity has been reported for NM_002524.4:c.291-8G>A in ClinVar submissions or the published literature. Details ▾Hide ▴
Evidence considered
- Exploratory literature and ClinVar review found no de novo reports for this variant.
Still missing
- No trio-based exome/genome studies mentioning c.291-8G>A as a de novo finding.
Sources
clinvar ↗22220252
PS3 No functional studies from the VCEP-approved assay list (RAS activation, MEK/ERK activation assays) have been performed on c.291-8G>A. SpliceAI predicts no splicing impact (max delta 0.01), consistent with no functional consequence. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.01 predicts no splice impact
- no VCEP-approved functional assays reported for this variant
- approved NRAS functional study PMIDs (19966803
- 28594414
- 21263000) do not include this variant.
Still missing
- No minigene
- RNA analysis
- or protein activity assay directly testing the effect of c.291-8G>A.
Sources
PS4 The variant is present in gnomAD at 167/1,607,416 alleles (v4.1, AF=0.010%), including one homozygote. This population frequency argues against significant enrichment in RASopathy cases. No case-control study demonstrates case enrichment. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 18/282
- 784 alleles (AF=0.0064%
- FAF=0.0047%)
- gnomAD v4.1: 167/1
- 607
- 416 alleles (AF=0.010%
- FAF=0.010%)
- 1 homozygote
- described as common benign polymorphism in PMID 24806883 per exploratory review.
Still missing
- No formal case-control odds ratio calculated.
Sources
PM2 VCEP PM2 requires the variant be absent from gnomAD. c.291-8G>A is present in gnomAD v2.1 (18/282,784 alleles, AF=0.0064%) and v4.1 (167/1,607,416 alleles, AF=0.010%), including one homozygous individual. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 18 alleles (AF=6.37e-05)
- gnomAD v4.1: 167 alleles (AF=1.04e-04)
- 1 homozygote. Variant is not absent from population controls.
Sources
PM6 No assumed de novo observation (without confirmed parentage) has been reported for this variant in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No ClinVar submission marked as de novo
- no literature report of de novo occurrence with or without parentage confirmation.
Still missing
- No assumed de novo reports in any available source.
Sources
clinvar ↗22220252
PP1 No cosegregation data with disease in multiple affected family members has been reported for c.291-8G>A. The VCEP requires >=3 informative meioses for Supporting strength. Details ▾Hide ▴
Evidence considered
- Exploratory search found no published cosegregation data
- variant is intronic and common in population
- making familial segregation studies unlikely.
Still missing
- No cosegregation data in families with multiple affected members.
PP3 SpliceAI predicts no splicing impact (max delta score = 0.01), which does not support a deleterious effect. The VCEP PP3 rule for splicing impact requires the predicted outcome to match the gain-of-function disease mechanism, which is not satisfied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01
- no predicted splice-altering effect. REVEL not applicable (intronic
- not missense).
Sources
BA1 VCEP BA1 requires gnomAD filtering allele frequency >= 0.05%. gnomAD v2.1 grpmax FAF = 0.0047% and v4.1 grpmax FAF = 0.010%, both well below the 0.05% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 FAF=4.74e-05 (0.0047%)
- gnomAD v4.1 FAF=9.99e-05 (0.010%). Both below VCEP BA1 threshold of 0.05%.
Sources
BS1 VCEP BS1 requires gnomAD filtering allele frequency >= 0.025%. gnomAD v2.1 grpmax FAF = 0.0047% and v4.1 grpmax FAF = 0.010%, both below the 0.025% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 FAF=4.74e-05 (0.0047%)
- gnomAD v4.1 FAF=9.99e-05 (0.010%). Both below VCEP BS1 threshold of 0.025%.
Sources
BS2 No observation of this variant in a healthy adult individual (homozygous or heterozygous) with documented unaffected clinical status has been reported. gnomAD homozygote count alone is insufficient without phenotype data. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 reports 1 homozygote
- but no clinical phenotype data are available to confirm unaffected status.
Still missing
- No documented healthy adult homozygous or heterozygous carrier with confirmed unaffected phenotype.
Sources
BS4 No published data demonstrate lack of segregation of c.291-8G>A in affected members of a family. The VCEP requires only one informative meiosis, but none are documented. Details ▾Hide ▴
Evidence considered
- Exploratory search found no segregation data for this variant.
Still missing
- No family-based segregation analysis has been reported.
BP2 No evidence of c.291-8G>A observed in trans with a known pathogenic NRAS variant, or as an alternative molecular cause for a RASopathy phenotype. Details ▾Hide ▴
Evidence considered
- Exploratory search found no co-occurrence data with pathogenic NRAS variants
- no phased genotype data available.
Still missing
- No clinical report of c.291-8G>A in trans with an established pathogenic NRAS variant.
BP5 No alternative molecular cause for a RASopathy has been identified in cases carrying c.291-8G>A. Details ▾Hide ▴
Evidence considered
- No report of an alternative molecular diagnosis explaining the phenotype in carriers of this variant.
Still missing
- No case with alternative molecular cause documented.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPPVS1 is marked Not Applicable by the ClinGen RASopathy VCEP v2.3.0. Additionally, this intronic variant (c.291-8G>A) does not fall into the generic PVS1 null-variant buckets (nonsense, frameshift, or canonical +/-1,2 splice consensus). Details ▾Hide ▴
Evidence considered
- VCEP explicitly marks PVS1 as Not Applicable
- variant is deep intronic with no predicted protein truncation or canonical splice disruption.
Sources
PS1 N/APS1 requires the same amino acid change as a previously established pathogenic variant. c.291-8G>A is an intronic variant with no amino acid consequence (p.?), so PS1 cannot be applied. Details ▾Hide ▴
Evidence considered
- VCEP PS1 rule requires same amino acid change
- intronic variant produces no amino acid change.
Sources
PM1 N/AVCEP PM1 applies only to critical functional domains defined in the supplementary table (P-loop AA 10-17, SW1 AA 25-40, SW2 AA 57-64, SAK AA 145-156). c.291-8G>A is located in intron 2, far outside all defined functional domains. Details ▾Hide ▴
Evidence considered
- VCEP PM1 domain definitions restrict criterion to P-loop
- SW1
- SW2
- and SAK domains
- intronic variant lies outside all domains.
Sources
cspec ↗vcep_alignment_with_pm1_domains_pptx
PM5 N/APM5 requires a missense change at a residue with a previously established (likely) pathogenic missense variant. c.291-8G>A is an intronic variant with no protein consequence; pm5_candidates confirms the variant class is not missense-like. Details ▾Hide ▴
Evidence considered
- pm5_candidates report: variant class is not missense-like
- no eligible same-residue comparator variants exist.
Sources
cspec ↗pm5_candidates
PP2 VCEPVCEP explicitly marks PP2 as Not Applicable because the missense z-score for NRAS is <3.09 in gnomAD. Details ▾Hide ▴
Evidence considered
- VCEP PP2 applicability: Not Applicable due to low missense constraint (z-score <3.09).
Sources
PP4 VCEPVCEP explicitly marks PP4 as Not Applicable for this VCEP (see PS4 instead). Details ▾Hide ▴
PP5 VCEPVCEP explicitly marks PP5 as Not Applicable for this VCEP, per ClinGen SVI VCEP Review Committee recommendation. Details ▾Hide ▴
BS3 VCEPVCEP explicitly marks BS3 as Not Applicable for this VCEP. Details ▾Hide ▴
BP1 N/AVCEP BP1 applies only to truncating variants (nonsense, frameshift, canonical splice sites, initiation codon, entire gene or multi-exon deletion). c.291-8G>A is a deep intronic substitution and is not truncating. Details ▾Hide ▴
Evidence considered
- VCEP BP1 restricts applicability to truncating LOF variants
- c.291-8G>A is an intronic substitution.
Sources
PS5 N/APS5 requires the same nucleotide change as a previously established pathogenic variant. c.291-8G>A is a deep intronic substitution; no pathogenic variant has been established at this same nucleotide position. Details ▾Hide ▴
Evidence considered
- No known pathogenic variant at NRAS c.291-8 position
- intronic site is not a recognized pathogenic locus.
Sources
Identifiers
- Gene
- NRAS
- Transcript
- NM_002524.4
- Coding (HGVS c.)
- NM_002524.4:c.291-8G>A
- Protein (HGVS p.)
- NP_002515.1:p.?
- GRCh38
- chr1:114709736 C>T
- GRCh37
- chr1:115252357 C>T
- ClinVar
- 44575
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
167 / 1,607,416 alleles
AF 0.000104 · 1 homozygotes · FAF 9.99e-05
gnomAD v2.1
18 / 282,784 alleles
AF 6.37e-05 · 0 homozygotes · FAF 4.74e-05
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 0.0001 · 167 / 1,607,416 alleles · 1 hom · FAF 0.0001
| African/African American11 / 74,782 | 0.000151 hom |
| Remaining individuals8 / 62,280 | 0.00013 |
| European (non-Finnish)136 / 1,174,060 | 0.00012 |
| South Asian9 / 90,922 | 9.9e-05 |
| Ashkenazi Jewish1 / 29,572 | 3.4e-05 |
| East Asian1 / 44,858 | 2.2e-05 |
| Admixed American1 / 59,982 | 1.7e-05 |
0 alternate alleles recorded in 3 other groups: European (Finnish), Amish, Middle Eastern.
gnomAD v2.1
AF 6.4e-05 · 18 / 282,784 alleles · 0 hom · FAF 4.7e-05
| Remaining individuals1 / 7,222 | 0.00014 |
| East Asian2 / 19,954 | 0.0001 |
| European (non-Finnish)11 / 129,138 | 8.5e-05 |
| African/African American2 / 24,966 | 8e-05 |
| South Asian2 / 30,600 | 6.5e-05 |
0 alternate alleles recorded in 3 other groups: Admixed American, Ashkenazi Jewish, European (Finnish).
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000103893; MAF= 0.01039%, 167/1607416 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.000147094; MAF= 0.01471%, 11/74782 alleles, homozygotes = 1); grpmax FAF= 9.991e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.36528e-05; MAF= 0.00637%, 18/282784 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138466; MAF= 0.01385%, 1/7222 alleles, homozygotes = 0); grpmax FAF= 4.736e-05.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingSpliceAI predicts no splicing impact (max delta score = 0.01). The predicted splicing outcome is negligible and does not support a gain-of-function disease mechanism for RASopathies. Per VCEP BP4 instructions, this criterion is applicable for splicing variants where the predicted outcome is negligible or does not match the disease mechanism. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01
- predicting no splice-altering effect
- REVEL not applicable for intronic variant
- multiple computational lines (SpliceAI) consistently predict no impact.
Sources
BP7 Supportingc.291-8G>A is an intronic variant at position -8 from exon 3 (not a canonical splice site). SpliceAI predicts no impact to the splice consensus sequence nor the creation of a new splice site (max delta = 0.01). Per VCEP BP7, this rule is applicable for intronic positions except canonical splice sites and should be used in conjunction with BP4. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01
- no predicted donor/acceptor gain or loss
- variant is at intronic position -8
- not at a canonical +/-1
- 2 splice site.
Sources
PP3 SpliceAI predicts no splicing impact (max delta score = 0.01), which does not support a deleterious effect. The VCEP PP3 rule for splicing impact requires the predicted outcome to match the gain-of-function disease mechanism, which is not satisfied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01
- no predicted splice-altering effect. REVEL not applicable (intronic
- not missense).
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
10 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 22220252 ↗Prognostic Significance of NRAS Gene Mutations in Children with Acute Myelogenous Leukemia.Aly RM et al. · 2011No paper-specific finding is recorded.
-
PMID 24033266 ↗A systematic approach to assessing the clinical significance of genetic variants.No paper-specific finding is recorded.
-
PMID 26980726 ↗Comprehensive mutational profiling of core binding factor acute myeloid leukemia.Duployez N et al. · 2016No paper-specific finding is recorded.
-
PMID 27276561 ↗Genomic Classification and Prognosis in Acute Myeloid Leukemia.Papaemmanuil E et al. · 2016No paper-specific finding is recorded.
-
PMID 29692343 ↗Clonal interference of signaling mutations worsens prognosis in core-binding factor acute myeloid leukemia.Itzykson R et al. · 2018No paper-specific finding is recorded.
-
PMID 17671181 ↗Oncogenic NRAS, KRAS, and HRAS exhibit different leukemogenic potentials in mice.Parikh C et al. · 2007No paper-specific finding is recorded.
-
PMID 23325582 ↗Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer.Peeters M et al. · 2013No paper-specific finding is recorded.
-
PMID 23708912 ↗NRAS mutations with low allele burden have independent prognostic significance for patients with lower risk myelodysplastic syndromes.Murphy DM et al. · 2013No paper-specific finding is recorded.
-
PMID 27069254 ↗The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia.Arber DA et al. · 2016No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
167 / 1,607,416 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
3 Likely benign · 1 Uncertain significance · 1 Benign
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/44575/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-115252357-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-114709736-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002524.4%3Ac.291-…
- OncoKB ↗www.oncokb.org/gene/NRAS/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=NRAS+c.291-8G%3EA
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= 0.000103893; MAF= 0.01039%, 167/1607416 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.000147094; MAF= 0.01471%, 11/74782 alleles, homozygotes = 1); grpmax FAF= 9.991e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.36528e-05; MAF= 0.00637%, 18/282784 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000138466; MAF= 0.01385%, 1/7222 alleles, homozygotes = 0); grpmax FAF= 4.736e-05.
ClinVar
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Uncertain significance (1 clinical laboratory) and as Benign (1 clinical laboratory) and as Likely Benign by ClinGen RASopathy Variant Curation Expert Panel (expert panel). (ClinVarID = 44575)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).