About NRAS
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
NRAS c.35G>A, p.(Gly12Asp)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen NRAS VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS1Strong
PS1 · strong
p.Gly12Asp (G12D) is the same amino acid change as a previously established pathogenic variant regardless of nucleotide change. G12D is a well-characterized oncogenic substitution in NRAS, KRAS, and HRAS, observed in thousands of somatic cancers (COSMIC n=1303) and reported as Pathogenic in ClinVar by 11 clinical laboratories. The VCEP explicitly authorizes PS1 at Strong for analogous pathogenic residue positions across HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2.
PS3Moderate
PS3 · moderate
Well-established in vitro and in vivo functional studies demonstrate a gain-of-function effect for NRAS G12D. The VCEP-approved RAS Activation Assay, MEK Activation Assay, and ERK Activation Assay are all applicable to NRAS. N-RasG12D shows increased GTP-bound Ras (RAF-RBD pulldown), constitutive MEK and ERK phosphorylation in multiple cell types, and transforming activity in focus formation assays. Mouse models with endogenous NrasG12D expression develop myeloproliferative neoplasms. G12D is validated as a pathogenic/likely pathogenic control in VCEP-approved ERK Activation Assay for HRAS, supporting functional analogy across RAS paralogs. At least two different approved assay types (RAS Activation and MEK/ERK Activation) demonstrate damaging effect.
PM1Moderate
PM1 · moderate
Gly12 is located within the P-loop domain (amino acids 10-17), a critical and well-established functional domain defined in the VCEP supplementary table. The P-loop is essential for GTP binding and RAS protein function. This domain has no benign variation and is a known mutational hotspot.
PM5Moderate
PM5 · moderate
At codon 12 of NRAS, multiple different missense changes have been established as pathogenic: G12V, G12C, G12S, and G12A are all recognized oncogenic substitutions. The VCEP PM5 Moderate rule is satisfied when ≥1 [likely] pathogenic residue change exists at the same codon. G12D represents a novel residue change at a codon with established pathogenic variants.
PP3Supporting
PP3 · supporting
REVEL score is 0.783, which meets the VCEP threshold of ≥0.7 for PP3_Supporting for missense variants. SpliceAI predicts no splice impact (max delta = 0.00), consistent with the variant's primary effect being at the protein level. The REVEL score indicates multiple lines of computational evidence support a deleterious effect.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for NRAS Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PS1 strong, PS3 moderate, PM1 moderate, PM5 moderate, PP3 supporting; no rule matched the adjudicated criteria.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
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. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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.
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.
26 criteria with recorded statuses: 5 met · 6 not met · 8 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_002524.5:c.35G>A (p.Gly12Asp) is located in the P-loop domain (AA 10-17), a critical GTP-binding domain defined by the ClinGen RASopathy VCEP as a well-established functional domain without benign variation.
p.Gly12Asp is the same amino acid change as well-established pathogenic variants across NRAS and other RAS paralogs. G12D is a canonical oncogenic substitution reported as Pathogenic in ClinVar by 11 clinical laboratories and observed in 1,303 somatic cancer samples in COSMIC.
Multiple VCEP-approved functional assays demonstrate that NRAS G12D is a gain-of-function variant. N-RasG12D exhibits increased GTP-bound Ras (RAS Activation Assay), constitutive MEK and ERK phosphorylation (MEK/ERK Activation Assays), and transforming activity in focus formation assays.
At codon 12, multiple different missense changes (G12V, G12C, G12S, G12A) have been established as pathogenic, satisfying PM5 at Moderate strength per the VCEP rule requiring at least one [likely] pathogenic residue change at the same codon.
REVEL score of 0.783 meets the VCEP PP3 threshold (≥0.7), indicating multiple lines of computational evidence support a deleterious effect. SpliceAI predicts no splice impact (max delta = 0.00).
This variant is present in gnomAD at extremely low frequency (v2.1: 0.0008%, 2/251,484 alleles; v4.1: 0.00105%, 17/1,613,956 alleles), with no homozygotes observed. The variant is absent from gnomAD-Canada. These frequencies are well below the VCEP BS1 (≥0.025%) and BA1 (≥0.05%) thresholds.
No criteria match.
Met · 5
PS1 Strongp.Gly12Asp (G12D) is the same amino acid change as a previously established pathogenic variant regardless of nucleotide change. G12D is a well-characterized oncogenic substitution in NRAS, KRAS, and HRAS, observed in thousands of somatic cancers (COSMIC n=1303) and reported as Pathogenic in ClinVar by 11 clinical laboratories. The VCEP explicitly authorizes PS1 at Strong for analogous pathogenic residue positions across HRAS, KRAS, MRAS, NRAS, RIT1, and RRAS2. Details ▾Hide ▴
PS3 ModerateWell-established in vitro and in vivo functional studies demonstrate a gain-of-function effect for NRAS G12D. The VCEP-approved RAS Activation Assay, MEK Activation Assay, and ERK Activation Assay are all applicable to NRAS. N-RasG12D shows increased GTP-bound Ras (RAF-RBD pulldown), constitutive MEK and ERK phosphorylation in multiple cell types, and transforming activity in focus formation assays. Mouse models with endogenous NrasG12D expression develop myeloproliferative neoplasms. G12D is validated as a pathogenic/likely pathogenic control in VCEP-approved ERK Activation Assay for HRAS, supporting functional analogy across RAS paralogs. At least two different approved assay types (RAS Activation and MEK/ERK Activation) demonstrate damaging effect. Details ▾Hide ▴
Evidence considered
- PMID:19075190: N-RasG12D used as positive control
- elevated Ras-GTP
- increased phospho-MEK and phospho-ERK
- transforming in focus formation assay
- PMID:18372904: N-RasG12D mouse model shows functional effects in colonic epithelium (apoptosis resistance)
- PMID:23687087: NrasG12D/+ HSCs show hyperproliferation
- increased self-renewal
- constitutive ERK1/2 activation
- VCEP approved RAS Activation
- MEK Activation
- and ERK Activation assays for NRAS
- G12D is a well-established activating mutation
Sources
PM1 ModerateGly12 is located within the P-loop domain (amino acids 10-17), a critical and well-established functional domain defined in the VCEP supplementary table. The P-loop is essential for GTP binding and RAS protein function. This domain has no benign variation and is a known mutational hotspot. Details ▾Hide ▴
PM5 ModerateAt codon 12 of NRAS, multiple different missense changes have been established as pathogenic: G12V, G12C, G12S, and G12A are all recognized oncogenic substitutions. The VCEP PM5 Moderate rule is satisfied when ≥1 [likely] pathogenic residue change exists at the same codon. G12D represents a novel residue change at a codon with established pathogenic variants. Details ▾Hide ▴
PP3 SupportingREVEL score is 0.783, which meets the VCEP threshold of ≥0.7 for PP3_Supporting for missense variants. SpliceAI predicts no splice impact (max delta = 0.00), consistent with the variant's primary effect being at the protein level. The REVEL score indicates multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.783 (meets VCEP PP3 threshold ≥0.7)
- SpliceAI max delta: 0.00 (no splice impact)
Sources
Not met · 6 · evaluated, threshold not reached
PM2 The VCEP PM2 rule states the variant must be absent from controls in gnomAD. This variant is present in gnomAD v2.1 at AF=7.95e-06 (2/251,484 alleles) and in gnomAD v4.1 at AF=1.05e-05 (17/1,613,956 alleles). Although at extremely low frequency, the variant is not absent, so PM2_Supporting is not met under the strict VCEP definition. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.0008% (2/251
- 484
- 0 homozygotes)
- gnomAD v4.1: AF=0.00105% (17/1
- 613
- 956
- VCEP requires absence from gnomAD
- variant is present at extremely low frequency
Sources
BA1 The VCEP BA1 threshold is gnomAD filtering allele frequency ≥0.05%. This variant has AF=0.0008% in gnomAD v2.1 and AF=0.00105% in v4.1, both well below the BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.0008% << BA1 threshold of 0.05%
- gnomAD v4.1 AF=0.00105% << BA1 threshold of 0.05%
Sources
BS1 The VCEP BS1 threshold is gnomAD filtering allele frequency ≥0.025%. This variant has AF=0.0008% in gnomAD v2.1 and AF=0.00105% in v4.1, both well below the BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.0008% << BS1 threshold of 0.025%
- gnomAD v4.1 AF=0.00105% << BS1 threshold of 0.025%
Sources
BP1 The VCEP BP1 rule applies only to truncating variants (nonsense, frameshift, canonical splice site, initiation codon, entire gene or multi-exon deletion) in genes without established LOF correlation to disease. NM_002524.5:c.35G>A is a missense variant and does not qualify. Details ▾Hide ▴
Evidence considered
- VCEP BP1 applies only to truncating variants
- this is a missense variant
Sources
BP4 The VCEP BP4 threshold for missense variants is REVEL ≤0.3. The REVEL score for this variant is 0.783, which exceeds the BP4 threshold and instead meets PP3. Details ▾Hide ▴
BP7 BP7 applies only to synonymous (silent) variants. NM_002524.5:c.35G>A is a missense variant (p.Gly12Asp), not a synonymous change. Details ▾Hide ▴
Not assessed · 8 · no assessment recorded
PS2 No de novo occurrence data with confirmed maternity and paternity is available in the evidence packet for this specific variant. The VCEP PS2 point-based scoring requires confirmed de novo status with RASopathy phenotypes. Details ▾Hide ▴
Still missing
- No de novo reports with confirmed parentage identified
PS4 The VCEP PS4 requires point-based scoring using probands with RASopathy phenotypes. While this variant is observed in numerous somatic cancer cases and ClinVar submissions, the evidence packet does not contain specific germline RASopathy proband counts meeting VCEP phenotypic specifications for PS4 scoring. Details ▾Hide ▴
Evidence considered
- COSMIC reports 1303 somatic observations but these are not germline RASopathy probands
- ClinVar submissions lack individual proband-level phenotypic detail needed for PS4 scoring
Still missing
- No germline RASopathy proband counts with phenotypic detail available
PM6 No assumed de novo events are documented in the evidence packet for this variant. The VCEP PM6 requires point-based scoring with phenotypic specifications, and no data meeting these criteria were identified. Details ▾Hide ▴
Still missing
- No assumed de novo reports identified
PP1 No co-segregation data in affected family members is available. The VCEP PP1 requires ≥3 informative meioses for Supporting, ≥5 for Moderate, and ≥7 for Strong strength. Details ▾Hide ▴
Still missing
- No family segregation data available
BS2 No data on healthy adult individuals carrying this variant with full penetrance expected at an early age are available. The VCEP BS2 uses point-based scoring based on phenotypic specifications. Details ▾Hide ▴
Still missing
- No data on healthy individuals with this variant
BS4 No lack of segregation data in affected family members is available. The VCEP BS4 requires only one informative meiosis but no such data are present. Details ▾Hide ▴
Still missing
- No segregation data available
BP2 No data on an alternative molecular cause of a RASopathy in the same gene or on co-occurrence with a different causative variant are available. The VCEP BP2 uses point-based scoring for alternative molecular causes. Details ▾Hide ▴
Still missing
- No data on alternative molecular causes
BP5 No data on an alternative molecular cause of disease in a different gene are available. The VCEP BP5 uses point-based scoring for phenotypes inconsistent with RASopathy and fully explained by a different causative variant. Details ▾Hide ▴
Still missing
- No data on alternative molecular causes in different genes
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 VCEPNM_002524.5:c.35G>A is a missense variant (p.Gly12Asp). The ClinGen RASopathy VCEP v2.3.0 specifies PVS1 as not applicable; this variant does not fall into null-variant buckets (nonsense, frameshift, or canonical splice site). Details ▾Hide ▴
PP2 VCEPThe VCEP declares PP2 not applicable because the NRAS missense z-score in gnomAD is less than 3.09, indicating the gene does not have a low rate of benign missense variation. Details ▾Hide ▴
PP4 VCEPThe VCEP declares PP4 not applicable; see PS4 for phenotype-based evidence. Details ▾Hide ▴
PP5 VCEPThe VCEP explicitly declares PP5 not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BS3 VCEPThe VCEP declares BS3 not applicable for NRAS. Well-established functional studies for NRAS G12D uniformly show a damaging/gain-of-function effect. Details ▾Hide ▴
BP6 VCEPThe VCEP explicitly declares BP6 not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
PS5 N/AThe ClinGen RASopathy VCEP explicitly disables PP5 as not for use, and PS5 is not defined in the VCEP criteria. Applying the VCEP's intent consistently, PS5 is not applicable under this framework. Details ▾Hide ▴
Identifiers
- Gene
- NRAS
- Transcript
- NM_002524.5
- Coding (HGVS c.)
- NM_002524.5:c.35G>A
- Protein (HGVS p.)
- NP_002515.1:p.(Gly12Asp)
- GRCh38
- chr1:114716126 C>T
- GRCh37
- chr1:115258747 C>T
- ClinVar
- 39648, 3029607
- COSMIC
- COSV54736383
Gene diagram
Every interpreted variant in NRAS, mapped onto the exon structure of NM_002524.5. Select a row to find it on the plot.
NRASNM_002524.5
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 VCEP threshold of ≥0.7 for PP3_Supporting for missense variants. SpliceAI predicts no splice impact (max delta = 0.00), consistent with the variant's primary effect being at the protein level. The REVEL score indicates multiple lines of computational evidence support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.783 (meets VCEP PP3 threshold ≥0.7)
- SpliceAI max delta: 0.00 (no splice impact)
Sources
BP4 The VCEP BP4 threshold for missense variants is REVEL ≤0.3. The REVEL score for this variant is 0.783, which exceeds the BP4 threshold and instead meets PP3. Details ▾Hide ▴
BP7 BP7 applies only to synonymous (silent) variants. NM_002524.5:c.35G>A is a missense variant (p.Gly12Asp), not a synonymous change. Details ▾Hide ▴
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. 4 cited in the classification.
Cited in the classification
-
PMID 18372904 ↗Differential effects of oncogenic K-Ras and N-Ras on proliferation, differentiation and tumor progression in the colon.N-RasG12D expression in murine colonic epithelium did not alter basal growth properties but conferred resistance to DSS-induced apoptosis. In the context of Apc-mutant tumors, N-RasG12D did not promote tumor progression, contrasting with K-RasG12D which drove hyperplasia and loss of differentiation.→ PS3 Names this variant
Source detail
N-RasG12D did not alter the growth properties of the epithelium, but was able to confer resistance to apoptosis.
Location Results; Figures 1-3
Context Fabpl-Cre;NrasLSL-G12D/+ mouse model, colonic epithelium, in vivo
-
PMID 19075190 ↗High-throughput sequencing screen reveals novel, transforming RAS mutations in myeloid leukemia patients.Tyner JW et al. · 2009 Feb 19N-RasG12D was used as a positive control in RAS functional characterization. It exhibited elevated Ras-GTP levels (RAF-RBD pulldown), increased phospho-MEK and phospho-ERK, and transforming activity in A31 focus formation assays, serving as the most active mutant in the study's hierarchy.→ PS3 Names this variant
Source detail
the G12D substitution in both N-Ras and K-Ras induces higher levels of the GTP-bound state of the enzyme
Location Results; Figure 1A-B, Figure 2A
Context HEK293T/17 cells, RAF-RBD pulldown, MEK/ERK immunoblotting, A31 focus formation assay
-
PMID 23687087 ↗Nras(G12D/+) promotes leukemogenesis by aberrantly regulating hematopoietic stem cell functions.Endogenous NrasG12D/+ expression in hematopoietic stem cells induced moderate hyperproliferation, increased self-renewal, and myeloid differentiation bias. ERK1/2 was constitutively hyperactivated in NrasG12D/+ HSCs, and MEK inhibition with AZD6244 attenuated the aberrant HSC phenotypes.→ PS3 Names this variant
Source detail
ERK1/2 is constitutively hyperactivated in NrasG12D/+ HSCs and downregulation of the MEK/ERK signaling attenuates NrasG12D/+ HSC phenotypes.
Location Results; Figures 1-2
Context Mx1-Cre; NrasG12D/+ mouse model, hematopoietic stem cells, phospho-flow cytometry, MEK inhibitor AZD6244
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PMID 25252692 ↗Mutation-specific RAS oncogenicity explains NRAS codon 61 selection in melanoma.Comparison of NrasG12D and NrasQ61R in melanoma models showed that physiologic NrasG12D expression did not efficiently promote melanoma in vivo, in contrast to NrasQ61R and KrasG12D. NrasG12D showed enhanced nucleotide binding but decreased GTPase activity compared to wild-type, with similar engagement of PI3K and RAF effector pathways as NrasQ61R.→ PS3 Names this variant
Source detail
NrasG12D did not efficiently promote melanoma in vivo, whereas NrasQ61R expression efficiently promoted melanoma
Location Results; Figures 1-2, Table 2
Context Tyr-CRE-ERT2; p16L/L; LSL-NrasG12D mouse model, in vitro nucleotide binding and effector engagement assays
Other recorded publications
-
PMID 21586752 ↗Endogenous oncogenic Nras mutation initiates hematopoietic malignancies in a dose- and cell type-dependent manner.Wang J et al. · 2011No paper-specific finding is recorded.
-
PMID 16434492 ↗Implications of NRAS mutations in AML: a study of 2502 patients.Bacher U et al. · 2006No paper-specific finding is recorded.
-
PMID 23334668 ↗The genomic landscape of hypodiploid acute lymphoblastic leukemia.Holmfeldt L et al. · 2013This study of hypodiploid ALL identified NRAS pathway alterations including an inherited NRAS p.Gly12Ser substitution in one near-haploid case. NRAS p.Gly12Asp was not identified in this paper.Does not name this variant
Quoted passage
An NRAS p.Gly12Ser substitution was identified in remission DNA from case SJHYPO020
Results; Supplementary Table 12
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_002524.5%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.