rs267606921
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong
The NM_002524.5(NRAS):c.149C>T(p.Thr50Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000733 in 1,364,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 7.3e-7 ( 0 hom. )
Consequence
NRAS
NM_002524.5 missense
NM_002524.5 missense
Scores
6
6
7
Clinical Significance
Conservation
PhyloP100: 9.87
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 14 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002524.5
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.862
PP5
?
Variant 1-114713941-G-A is Pathogenic according to our data. Variant chr1-114713941-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-114713941-G-A is described in Lovd as [Likely_pathogenic]. Variant chr1-114713941-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NRAS | NM_002524.5 | c.149C>T | p.Thr50Ile | missense_variant | 3/7 | ENST00000369535.5 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NRAS | ENST00000369535.5 | c.149C>T | p.Thr50Ile | missense_variant | 3/7 | 1 | NM_002524.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 7.33e-7 AC: 1AN: 1364650Hom.: 0 Cov.: 31 AF XY: 0.00000148 AC XY: 1AN XY: 676466
GnomAD4 exome
AF:
AC:
1
AN:
1364650
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Cov.:
31
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AC XY:
1
AN XY:
676466
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GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
RASopathy Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 11, 2022 | Variant summary: NRAS c.149C>T (p.Thr50Ile) results in a non-conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251196 control chromosomes (gnomAD). c.149C>T has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (Cirstea_2010, Denayer_2012, Altmuller_2017, Rodriguez_2018, Li_2019), including at least one confirmed de novo occurrence (Rodriguez_2018). These data indicate that the variant is very likely to be associated with disease. In zebrafish embryos the variant resulted in severe developmental defects during epiboly and gastrulation that resembled the defects observed with known Noonan-associated genes (Runtuwene_2011). Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2022 | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 50 of the NRAS protein (p.Thr50Ile). This missense change has been observed in individual(s) with Noonan Syndrome (PMID: 19966803, 22855653). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NRAS function (PMID: 19966803, 21263000). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 13902). - |
Noonan syndrome 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2010 | - - |
Noonan syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 06, 2013 | The Thr50Ile variant has been reported in 2 individuals with clinical features o f Noonan syndrome (Cirstea 2010). This variant was reported to have occurred de novo in these individuals. Studies have shown that the Thr50Ile variant may impa ct protein function (Cirstea 2010, Runtuwene 2011). However, this in vitro assay may not accurately represent biological function. Computational analyses (bioch emical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) also suggest that the Thr50Ile variant may impact the protein, though this informati on is not predictive enough to determine pathogenicity. In summary, this varian t meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/L MM). - |
Noonan syndrome 1 Other:1
not provided, no classification provided | literature only | GeneReviews | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Uncertain
D
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
T
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Benign
N
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Loss of sheet (P = 0.1158);
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