rs121913250
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_002524.5(NRAS):c.34G>T(p.Gly12Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G12A) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 32)
Consequence
NRAS
NM_002524.5 missense
NM_002524.5 missense
Scores
10
6
3
Clinical Significance
Conservation
PhyloP100: 7.91
Genes affected
NRAS (HGNC:7989): (NRAS proto-oncogene, GTPase) This is an N-ras oncogene encoding a membrane protein that shuttles between the Golgi apparatus and the plasma membrane. This shuttling is regulated through palmitoylation and depalmitoylation by the ZDHHC9-GOLGA7 complex. The encoded protein, which has intrinsic GTPase activity, is activated by a guanine nucleotide-exchange factor and inactivated by a GTPase activating protein. Mutations in this gene have been associated with somatic rectal cancer, follicular thyroid cancer, autoimmune lymphoproliferative syndrome, Noonan syndrome, and juvenile myelomonocytic leukemia. [provided by RefSeq, Jun 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM1
In a binding_site (size 8) in uniprot entity RASN_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_002524.5
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr1-114716126-C-G is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.973
PP5
Variant 1-114716127-C-A is Pathogenic according to our data. Variant chr1-114716127-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 40468.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NRAS | NM_002524.5 | c.34G>T | p.Gly12Cys | missense_variant | 2/7 | ENST00000369535.5 | NP_002515.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NRAS | ENST00000369535.5 | c.34G>T | p.Gly12Cys | missense_variant | 2/7 | 1 | NM_002524.5 | ENSP00000358548 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:11
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Myelodysplastic syndrome Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Chronic myelogenous leukemia, BCR-ABL1 positive Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Druker Lab, Oregon Health and Sciences University | Oct 10, 2022 | - - |
Multiple myeloma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Malignant neoplasm of body of uterus Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Gastric adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Melanoma Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Dec 26, 2014 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 02, 2012 | This variant is denoted as p.Gly12Cys (GGT>TGT): c.34 G>T in exon 2 of NRAS. The G12C missense mutation has not be reported as a benign polymorphism or as a disease-causing mutation, to our knowledge. The G12C missense change is a non-conservative amino acid substitution with a non-polar residue (Gly) being replaced by a polar residue (Cys). The position at which this substitution occurs is highly conserved in the protein and the gain of a Cysteine residue may affect disulfide bond formation in the protein. A different missense mutation this codon (G12V) has been reported previously as a somatic mutation in association with several different types of cancer (Catalogue of Somatic Mutations in Cancer; Cirstea et al., 2010), primarily in haematopoietic and lymphoid tissues. Another missense mutation at a neighboring codon (G13D) has been reported as a germline mutation (Filippi et al., 2009; Oliviera et al., 2007). In Filippi et al., the patient with the G13D mutation was described as having dysmorphic features (including macrocephaly, bilateral epicanthal folds and cafe-au-lait spots) in addition to clinical and hematological features consistent with a diagnosis of juvenile myelomonocytic leukemia (JMML) (Filippi et al., 2009). The presence of the G12C mutation is consistent with a diagnosis of an NRAS-related disorder and the reported diagnosis of JMML. The variant is found in NOONAN panel(s). - |
Non-small cell lung carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
Malignant melanoma of skin Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Acute myeloid leukemia Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of the large intestine Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Loss of disorder (P = 0.1073);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at