About NRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NRAS c.35G>A, p.(Gly12Asp)
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS1Strong
PS1 · strong
NM_002524.4:c.35G>A (p.Gly12Asp) is the same amino acid change as well-established pathogenic G12D variants in HRAS, KRAS, and other RAS genes, satisfying the RASopathy VCEP PS1 rule for analogous pathogenic residue positions. ClinVar classifies NRAS G12D as Pathogenic (11 clinical laboratories) and Likely pathogenic (3 laboratories).
PS4Supporting
PS4 · supporting
NRAS G12D has been observed in multiple probands with RASopathy-spectrum phenotypes. ClinVar reports 14 usable submissions including clinical laboratories classifying as Pathogenic. G12D is reported in juvenile myelomonocytic leukemia (JMML), a RASopathy-associated condition (PMID:17332249). Meeting VCEP PS4 threshold of at least 1 point (Supporting).
PM1Moderate
PM1 · moderate
Gly12 is located in the P-loop domain (amino acids 10-17), one of four critical and well-established functional domains specified by the RASopathy VCEP (P-loop, SW1, SW2, SAK). The P-loop is a mutational hotspot without benign variation, satisfying PM1 at Moderate strength.
PP3Supporting
PP3 · supporting
REVEL score is 0.783, which meets the RASopathy VCEP PP3 threshold of ≥0.7 for missense variants. SpliceAI predicts no splice impact (max delta=0.00), consistent with a missense mechanism rather than splicing effect. BayesDel score (0.329) is below typical pathogenic thresholds but REVEL is the specified VCEP metric.
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: PS1 strong, PS4 supporting, PM1 moderate, PP3 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
17 / 1,613,956 alleles
gnomAD v4.1: 17 / 1,613,956 alleles. Recorded AF 1.05331e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95279e-06; MAF= 0.00080%, 2/251484 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.61936e-05; MAF= 0.00462%, 1/21648 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
14 reported laboratory submissions
11 Pathogenic · 3 Likely pathogenic.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1303 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV54736383, n = 1303 times).
Cancer Hotspots
This variant lies 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.
25 criteria with recorded statuses: 4 met · 12 not met · 1 not assessed · 8 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.35G>A (p.Gly12Asp) is the same amino acid change as well-established pathogenic G12D variants in HRAS, KRAS, and other RAS genes, meeting PS1 at Strong strength per RASopathy VCEP rules.
Gly12 is located in the P-loop domain (amino acids 10-17), a VCEP-specified critical functional domain and mutational hotspot without benign variation, meeting PM1 at Moderate strength.
REVEL score of 0.783 meets the VCEP PP3 threshold of ≥0.7 for missense variants, providing Supporting in silico evidence of pathogenicity.
NRAS G12D has been observed in multiple probands with RASopathy-spectrum phenotypes including juvenile myelomonocytic leukemia, meeting PS4 at Supporting strength (≥1 point).
The variant is present at extremely low frequency in gnomAD (max AF=0.0046%), far below BA1 (0.05%) and BS1 (0.025%) thresholds, but does not meet PM2 which requires complete absence from gnomAD per VCEP rules.
Extensive functional evidence for NRAS G12D exists in the literature including mouse models and biochemical assays, but VCEP-approved functional assay verification for the specific variant in germline RASopathy context requires human review.
No criteria match.
Met · 4
PS1 StrongNM_002524.4:c.35G>A (p.Gly12Asp) is the same amino acid change as well-established pathogenic G12D variants in HRAS, KRAS, and other RAS genes, satisfying the RASopathy VCEP PS1 rule for analogous pathogenic residue positions. ClinVar classifies NRAS G12D as Pathogenic (11 clinical laboratories) and Likely pathogenic (3 laboratories). Details ▾Hide ▴
PS4 SupportingNRAS G12D has been observed in multiple probands with RASopathy-spectrum phenotypes. ClinVar reports 14 usable submissions including clinical laboratories classifying as Pathogenic. G12D is reported in juvenile myelomonocytic leukemia (JMML), a RASopathy-associated condition (PMID:17332249). Meeting VCEP PS4 threshold of at least 1 point (Supporting). Details ▾Hide ▴
Evidence considered
- ClinVar: Pathogenic by 11 clinical labs
- Likely pathogenic by 3 (ClinVarID 39648)
- NRAS codon 12 mutations found in 112/257 NRAS-mutated AML patients (PMID:16434492)
- NRAS G12D reported in JMML with spontaneous hematologic improvement (PMID:17332249)
- JMML-associated NRAS variants implicated in neonatal lethal Noonan syndrome (PMID:28098151)
Still missing
- Precise proband count with RASopathy phenotype not enumerated
Sources
PM1 ModerateGly12 is located in the P-loop domain (amino acids 10-17), one of four critical and well-established functional domains specified by the RASopathy VCEP (P-loop, SW1, SW2, SAK). The P-loop is a mutational hotspot without benign variation, satisfying PM1 at Moderate strength. Details ▾Hide ▴
Evidence considered
- VCEP PM1: Gly12 falls within P-loop (AA 10-17)
- a VCEP-approved critical functional domain
- Statistically significant hotspot (evidence_brief)
- COSMIC: 1303 somatic observations at this residue (COSV54736383)
Sources
PP3 SupportingREVEL score is 0.783, which meets the RASopathy VCEP PP3 threshold of ≥0.7 for missense variants. SpliceAI predicts no splice impact (max delta=0.00), consistent with a missense mechanism rather than splicing effect. BayesDel score (0.329) is below typical pathogenic thresholds but REVEL is the specified VCEP metric. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.783 (meets VCEP threshold of ≥0.7)
- SpliceAI max delta: 0.00 (no predicted splice impact)
- BayesDel score: 0.329
Sources
Not met · 12 · evaluated, threshold not reached
PS2 No de novo occurrence data (with confirmed maternity and paternity) is available for NM_002524.4:c.35G>A in this evidence packet. VCEP PS2 requires point-based scoring from documented de novo events. Details ▾Hide ▴
Evidence considered
- No de novo data available in ClinVar
- literature
- or case materials
Still missing
- De novo occurrence data with confirmed parentage not available
Sources
PM2 The RASopathy VCEP PM2 rule requires the variant to be absent from gnomAD controls. NM_002524.4:c.35G>A is present in gnomAD v2.1 (AF=7.95e-6; 2/251,484 alleles) and gnomAD v4.1 (AF=1.05e-5; 17/1,613,956 alleles). It does not meet the VCEP requirement for absence from controls. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 2/251
- 484 alleles (AF=7.95e-6)
- 0 homozygotes
- gnomAD v4.1: 17/1
- 613
- 956 alleles (AF=1.05e-5)
- grpmax FAF=7.63e-6
- VCEP PM2 requires complete absence from gnomAD
Sources
PM5 PM5 is designed for novel missense changes at a codon where a different pathogenic missense is already established. NM_002524.4:c.35G>A (p.Gly12Asp) is itself one of the most well-characterized pathogenic changes at codon 12, not a novel variant. Applying PM5 to the index pathogenic variant would constitute double-counting with PS1. Multiple other pathogenic changes at codon 12 (G12V, G12C, G12S, G12A, G12R) are well-established, but PM5 is not applied to the reference pathogenic change. Details ▾Hide ▴
Evidence considered
- G12D is an established pathogenic variant
- not a novel change at codon 12
- VCEP PM5 rule is intended for novel missense changes where a different pathogenic residue change exists at the same codon
Sources
PM6 No de novo data (without confirmation of maternity and paternity) is available for this variant. VCEP PM6 requires point-based scoring from de novo observations. No de novo events are reported in ClinVar, literature, or case materials. Details ▾Hide ▴
Evidence considered
- No de novo observations available in the evidence packet
Still missing
- De novo observation data not available
Sources
PP1 No segregation data is available for NM_002524.4:c.35G>A. VCEP PP1 requires at least 3 informative meioses for Supporting strength. No family studies or cosegregation data are present in the evidence packet. Details ▾Hide ▴
Evidence considered
- No cosegregation or family study data available
Still missing
- Segregation/family study data not available
Sources
BA1 The maximum gnomAD filtering allele frequency for NM_002524.4:c.35G>A is 4.62e-5 (0.0046%) in the European (Finnish) subpopulation (v2.1) and grpmax FAF is 7.63e-6 (v4.1). These are far below the VCEP BA1 threshold of ≥0.05% (Stand Alone). The variant is too rare in population databases to meet BA1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpopulation AF: 0.0046% (European Finnish)
- gnomAD v4.1 grpmax FAF: 0.00076% (7.63e-6)
- VCEP BA1 threshold: ≥0.05%
Sources
BS1 The maximum gnomAD allele frequency for NM_002524.4:c.35G>A (0.0046%) is below the VCEP BS1 threshold of ≥0.025%. The variant is not sufficiently common in population databases to meet BS1 at Strong strength. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpopulation AF: 0.0046% (European Finnish)
- gnomAD v4.1 max subpopulation AF: 0.0034% (Ashkenazi Jewish)
- VCEP BS1 threshold: ≥0.025%
Sources
BS2 No data on healthy adult individuals carrying NM_002524.4:c.35G>A is available. VCEP BS2 uses point-based scoring requiring documented healthy homozygote or heterozygote individuals. No such observations are present in the evidence packet. Details ▾Hide ▴
Evidence considered
- No healthy adult carrier data available for point-based BS2 scoring
Still missing
- Healthy adult carrier data not available
Sources
BS4 No segregation data is available. VCEP BS4 requires at least one informative meiosis demonstrating lack of cosegregation with disease. No family studies are present in the evidence packet. Details ▾Hide ▴
Evidence considered
- No segregation or family study data available
Still missing
- Segregation data not available
Sources
BP2 No evidence of an alternative molecular cause for a RASopathy in the same gene is available. VCEP BP2 requires point-based scoring for an alternative molecular cause. No such data is present in the evidence packet. Details ▾Hide ▴
Evidence considered
- No alternative molecular cause data available
Still missing
- Alternative molecular cause data not available
Sources
BP4 REVEL score is 0.783, which does not meet the VCEP BP4 threshold of ≤0.3 for missense variants. Multiple in silico predictors support a deleterious effect rather than a benign impact. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.783 (does not meet BP4 threshold of ≤0.3)
- BayesDel score: 0.329
Sources
BP5 No evidence of an alternative molecular cause for disease is available. VCEP BP5 uses point-based scoring requiring an alternative molecular cause. No such observations are present in the evidence packet. Details ▾Hide ▴
Evidence considered
- No alternative molecular cause data available
Still missing
- Alternative molecular cause data not available
Sources
Not assessed · 1 · no assessment recorded
PS3 Extensive functional evidence for NRAS G12D as a gain-of-function variant exists in the literature (multiple mouse models, RAS activation assays, MEK/ERK phosphorylation assays, focus formation assays). OncoKB curates this variant as Oncogenic/Gain-of-function. However, specific VCEP-approved functional assay instances (RAS Activation Assay PMIDs: 19966803, 28594414, 21263000; MEK Activation Assay: same PMIDs) could not be verified for this exact variant. The approved full-text papers (PMID:19075190, 25252692, 21586752, 23687087, 18372904) demonstrate N-Ras G12D functional impact but are primarily somatic/cancer contexts, not germline RASopathy contexts. Needs human review to determine if these meet the VCEP PS3 threshold. Details ▾Hide ▴
Evidence considered
- OncoKB: Oncogenic
- Gain-of-function
- N-Ras G12D used as positive control in focus formation
- colony formation
- and RAF pull-down assays (PMID:19075190)
- N-Ras G12D activates MAPK pathway
- promotes leukemogenesis in mouse models (PMID:21586752
- 23687087)
- N-Ras G12D confers apoptosis resistance in colonic epithelium (PMID:18372904)
- N-Ras G12D less transforming than Q61R in melanoma but biochemically active (PMID:25252692)
Still missing
- Verification that VCEP-approved functional assay PMIDs (19966803
- 28594414
- 21263000) specifically test G12D
- Germline RASopathy-context functional data not confirmed
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPPVS1 is classified as Not Applicable by the ClinGen RASopathy VCEP for NRAS (v2.3.0). NM_002524.4:c.35G>A is a missense variant (p.Gly12Asp), not a null variant, and does not fall into any PVS1 variant bucket. Details ▾Hide ▴
PP2 VCEPPP2 is classified as Not Applicable by the ClinGen RASopathy VCEP for NRAS (v2.3.0). Details ▾Hide ▴
PP4 VCEPPP4 is classified as Not Applicable by the ClinGen RASopathy VCEP for NRAS (v2.3.0). Details ▾Hide ▴
PP5 VCEPPP5 is classified as Not Applicable by the ClinGen RASopathy VCEP for NRAS (v2.3.0). Details ▾Hide ▴
BS3 VCEPBS3 is classified as Not Applicable by the ClinGen RASopathy VCEP for NRAS (v2.3.0). Details ▾Hide ▴
BP1 N/ABP1 applies only to truncating variants (nonsense, frameshift, canonical splice site, initiation codon, or gene deletions) in genes where the disease mechanism is gain-of-function. NM_002524.4:c.35G>A is a missense variant (p.Gly12Asp), not a truncating variant. BP1 does not apply to missense changes. Details ▾Hide ▴
Evidence considered
- G12D is a missense variant
- BP1 is restricted to truncating variants per VCEP specification
Sources
BP6 VCEPBP6 is classified as Not Applicable by the ClinGen RASopathy VCEP for NRAS (v2.3.0). Details ▾Hide ▴
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_002524.4:c.35G>A is a missense variant (p.Gly12Asp), not a synonymous variant. BP7 does not apply to missense changes. Details ▾Hide ▴
Evidence considered
- G12D is a missense variant
- BP7 is restricted to synonymous and intronic variants per VCEP specification
Sources
Identifiers
- Gene
- NRAS
- Transcript
- NM_002524.4
- Coding (HGVS c.)
- NM_002524.4:c.35G>A
- Protein (HGVS p.)
- NP_002515.1:p.(Gly12Asp)
- GRCh38
- chr1:114716126 C>T
- GRCh37
- chr1:115258747 C>T
- ClinVar
- 39648
- COSMIC
- COSV54736383
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
17 / 1,613,956 alleles
AF 1.05e-05 · 0 homozygotes · FAF 7.63e-06
gnomAD v2.1
2 / 251,484 alleles
AF 7.95e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.1e-05 · 17 / 1,613,956 alleles · 0 hom · FAF 7.6e-06
| Ashkenazi Jewish1 / 29,598 | 3.4e-05 |
| European (non-Finnish)15 / 1,179,834 | 1.3e-05 |
| South Asian1 / 91,082 | 1.1e-05 |
0 alternate alleles recorded in 7 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, African/African American.
gnomAD v2.1
AF 8e-06 · 2 / 251,484 alleles · 0 hom
| European (Finnish)1 / 21,648 | 4.6e-05 |
| European (non-Finnish)1 / 113,762 | 8.8e-06 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.05331e-05; MAF= 0.00105%, 17/1613956 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37861e-05; MAF= 0.00338%, 1/29598 alleles, homozygotes = 0); grpmax FAF= 7.63e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95279e-06; MAF= 0.00080%, 2/251484 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.61936e-05; MAF= 0.00462%, 1/21648 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.783
- BayesDel
- 0.329
How the predictions were used
PP3 SupportingREVEL score is 0.783, which meets the RASopathy VCEP PP3 threshold of ≥0.7 for missense variants. SpliceAI predicts no splice impact (max delta=0.00), consistent with a missense mechanism rather than splicing effect. BayesDel score (0.329) is below typical pathogenic thresholds but REVEL is the specified VCEP metric. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.783 (meets VCEP threshold of ≥0.7)
- SpliceAI max delta: 0.00 (no predicted splice impact)
- BayesDel score: 0.329
Sources
BP4 REVEL score is 0.783, which does not meet the VCEP BP4 threshold of ≤0.3 for missense variants. Multiple in silico predictors support a deleterious effect rather than a benign impact. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.783 (does not meet BP4 threshold of ≤0.3)
- BayesDel score: 0.329
Sources
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_002524.4:c.35G>A is a missense variant (p.Gly12Asp), not a synonymous variant. BP7 does not apply to missense changes. Details ▾Hide ▴
Evidence considered
- G12D is a missense variant
- BP7 is restricted to synonymous and intronic variants per VCEP specification
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.783. BayesDel score = 0.328551.
7 paper records listed. 2 cited in the classification.
Cited in the classification
-
PMID 16434492 ↗Implications of NRAS mutations in AML: a study of 2502 patients.Bacher U et al. · 2006 May 15Analyzed 2502 AML patients for NRAS mutations at codons 12, 13, and 61. Most codon 12 mutations resulted in changes from glycine to asparagine (consistent with G12D being the most common). Reports 112/257 NRAS-mutated patients had codon 12 mutations, but does not enumerate G12D specifically by HGVS nomenclature.→ PS4 Does not name this variant
Source detail
Most mutations (112 of 257; 43.6%) were found at codon 12, mostly resulting in changes from glycine to asparagine
Location Abstract; Results, codon 12 mutation description
-
PMID 19075190 ↗High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients.Tyner JW et al. · 2009 Feb 19N-Ras G12D was used as a positive control in functional transformation assays (focus formation, colony formation, RAF pull-down) and was the most biochemically active mutant tested. NRAS G12D was also detected as a somatic mutation in 10 AML patients and 3 CMML patients in the screening cohort.→ PS4 Names this variant
Source detail
cells were infected with equivalent multiplicity of infection of retrovirus-expressing empty vector, N-Ras G12D, N-Ras WT
Location Methods (focus formation assay); Results; Table 1
Context A31 fibroblast focus formation assay, RAF-1 pull-down assay, murine bone marrow colony-forming assay, HEK 293T/17 cells
Other recorded publications
-
PMID 21586752 ↗Endogenous oncogenic Nras mutation initiates hematopoietic malignancies in a dose- and cell type-dependent manner.Wang J et al. · 2011Nras G12D knock-in mouse model demonstrates dose-dependent initiation of hematopoietic malignancies. Monoallelic and biallelic oncogenic Nras G12D expression leads to myeloproliferative neoplasm in mice.Names this variant
Quoted passage
NrasG12D/+ mice develop a chronic myeloproliferative neoplasm
Abstract; Results; throughout
-
PMID 18372904 ↗Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon.N-Ras G12D expression in mouse colonic epithelium did not alter basal proliferation but conferred resistance to DSS-induced apoptosis, in contrast to K-Ras G12D which promoted hyperproliferation via Mek-dependent signaling.Names this variant
Quoted passage
N-RasG12D did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis
Abstract; Results; Figure 1-3
-
PMID 23687087 ↗Nras(G12D/+) promotes leukemogenesis by aberrantly regulating hematopoietic stem cell functions.Endogenous Nras G12D/+ expression in hematopoietic cells leads to expansion of myeloid progenitors, increased long-term reconstitution of bone marrow cells, and chronic myeloproliferative neoplasm in mice.Names this variant
Quoted passage
expression of endogenous oncogenic Nras (NrasG12D/+) in hematopoietic cells leads to expansion of myeloid progenitors, increased long-term reconstitution of bone marrow cells, and a chronic myeloproliferative neoplasm (MPN)
Abstract; Results
-
PMID 25252692 ↗Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma.N-Ras G12D was compared to N-Ras Q61R and K-Ras G12D for melanomagenic potential. N-Ras G12D was significantly less transforming in melanocytes than N-Ras Q61R, with only 1 tumor in 29 mice over 80 weeks, demonstrating codon-specific oncogenicity. Biochemically, N-Ras G12D exhibited similar RAF-RBD and PI3K binding affinities to wild-type N-Ras.Names this variant
Quoted passage
N-RasG12D was not capable of immortalizing p16INK4a-deficient melanocytes
Abstract; Results; Figure 2; Table 1-2
-
PMID 23334668 ↗The genomic landscape of hypodiploid acute lymphoblastic leukemia.Holmfeldt L et al. · 2013Genomic profiling study of hypodiploid acute lymphoblastic leukemia identifying NRAS and KRAS mutations as recurrent alterations in the near-haploid subtype. NM_002524.4:c.35G>A was not specifically identified or discussed in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
17 / 1,613,956 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
11 Pathogenic · 3 Likely pathogenic
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/39648/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/1-115258747-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr1-114716126-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/1-114716126-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002524.4%3Ac.35G%…
- OncoKB ↗www.oncokb.org/gene/NRAS/G12D
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=136034166
- 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= 1.05331e-05; MAF= 0.00105%, 17/1613956 alleles, homozygotes = 0) and has highest observed frequency in the Ashkenazi Jewish population (AF= 3.37861e-05; MAF= 0.00338%, 1/29598 alleles, homozygotes = 0); grpmax FAF= 7.63e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95279e-06; MAF= 0.00080%, 2/251484 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.61936e-05; MAF= 0.00462%, 1/21648 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (11 clinical laboratories) and as Likely pathogenic (3 clinical laboratories). (ClinVarID = 39648)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.783. BayesDel score = 0.328551.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Gain-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV54736383, n = 1303 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.