rs121917759
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_005343.4(HRAS):c.437C>T(p.Ala146Val) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A146P) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 33)
Consequence
HRAS
NM_005343.4 missense
NM_005343.4 missense
Scores
14
3
1
Clinical Significance
Conservation
PhyloP100: 9.77
Genes affected
HRAS (HGNC:5173): (HRas proto-oncogene, GTPase) This gene belongs to the Ras oncogene family, whose members are related to the transforming genes of mammalian sarcoma retroviruses. The products encoded by these genes function in signal transduction pathways. These proteins can bind GTP and GDP, and they have intrinsic GTPase activity. This protein undergoes a continuous cycle of de- and re-palmitoylation, which regulates its rapid exchange between the plasma membrane and the Golgi apparatus. Mutations in this gene cause Costello syndrome, a disease characterized by increased growth at the prenatal stage, growth deficiency at the postnatal stage, predisposition to tumor formation, cognitive disability, skin and musculoskeletal abnormalities, distinctive facial appearance and cardiovascular abnormalities. Defects in this gene are implicated in a variety of cancers, including bladder cancer, follicular thyroid cancer, and oral squamous cell carcinoma. Multiple transcript variants, which encode different isoforms, have been identified for this gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PM1
In a chain GTPase HRas, N-terminally processed (size 184) in uniprot entity RASH_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) in NM_005343.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr11-533467-C-G is described in Lovd as [Likely_pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 11-533466-G-A is Pathogenic according to our data. Variant chr11-533466-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-533466-G-A is described in UniProt as null. Variant chr11-533466-G-A is described in UniProt as null. Variant chr11-533466-G-A is described in UniProt as null.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| HRAS | NM_005343.4 | c.437C>T | p.Ala146Val | missense_variant | 4/6 | ENST00000311189.8 | NP_005334.1 | |
| HRAS | NM_176795.5 | c.437C>T | p.Ala146Val | missense_variant | 4/6 | ENST00000417302.7 | NP_789765.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| HRAS | ENST00000311189.8 | c.437C>T | p.Ala146Val | missense_variant | 4/6 | 1 | NM_005343.4 | ENSP00000309845 | P1 | |
| HRAS | ENST00000417302.7 | c.437C>T | p.Ala146Val | missense_variant | 4/6 | 5 | NM_176795.5 | ENSP00000388246 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 35
GnomAD4 exome
Cov.:
35
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Costello syndrome Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 29, 2018 | This sequence change replaces alanine with valine at codon 146 of the HRAS protein (p.Ala146Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with attenuated Costello syndrome (PMID: 18247425). ClinVar contains an entry for this variant (Variation ID: 12611). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The p.Ala146 amino acid residue in HRAS has been determined to be clinically significant (PMID: 17054105, 28328122). This suggests that variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 26, 2013 | The Ala146Val variant in HRAS has been reported in one individual with mild clin ical features of Costello syndrome (Gripp 2008), and was absent in large populat ion studies. In addition, another variant at the Ala146 residue (Ala146Thr) has also been identified as occurring de novo in one individual with mild clinical f eatures of Costello syndrome (Zampino 2007). Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, MAPP, PolyPhen2, and SIFT) sugg est that this variant may impact the protein, though this information is not pre dictive enough to determine pathogenicity. In summary, this variant is likely pa thogenic, though additional studies are required to fully establish its clinical significance. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 15, 2008 | - - |
Multiple myeloma 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 | - - |
Lung adenocarcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | May 31, 2016 | - - |
Neoplasm of uterine cervix 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
| 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 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Pathogenic
.;D;.;D;D
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;M;M
MutationTaster
Benign
A;A;A;A;A
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
D;D;D;D;D
Vest4
MutPred
Loss of ubiquitination at K147 (P = 0.0692);Loss of ubiquitination at K147 (P = 0.0692);Loss of ubiquitination at K147 (P = 0.0692);Loss of ubiquitination at K147 (P = 0.0692);Loss of ubiquitination at K147 (P = 0.0692);
MVP
MPC
2.0
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