rs104894230
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_005343.4(HRAS):c.35G>T(p.Gly12Val) 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. G12E) has been classified as Likely pathogenic.
Frequency
Genomes: not found (cov: 34)
Consequence
HRAS
NM_005343.4 missense
NM_005343.4 missense
Scores
11
5
2
Clinical Significance
Conservation
PhyloP100: 7.82
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PM1
In a strand (size 3) in uniprot entity RASH_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) 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 chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.981
PP5
Variant 11-534288-C-A is Pathogenic according to our data. Variant chr11-534288-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 12600.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| HRAS | NM_005343.4 | c.35G>T | p.Gly12Val | missense_variant | 2/6 | ENST00000311189.8 | NP_005334.1 | |
| HRAS | NM_176795.5 | c.35G>T | p.Gly12Val | missense_variant | 2/6 | ENST00000417302.7 | NP_789765.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| HRAS | ENST00000311189.8 | c.35G>T | p.Gly12Val | missense_variant | 2/6 | 1 | NM_005343.4 | ENSP00000309845 | P1 | |
| HRAS | ENST00000417302.7 | c.35G>T | p.Gly12Val | missense_variant | 2/6 | 5 | NM_176795.5 | ENSP00000388246 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
34
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
34
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Costello syndrome Pathogenic:5
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jan 07, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 21, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | Jun 04, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 05, 2011 | The Gly12Val variant in HRAS has been reported in the literature in a proband wi th Costello syndrome and was verified to have occured de novo in that individual (Aoki 2005). While the reported proband had an alternate DNA change (c.35_36del insTT), the predicted protein change is identical to that predicted for this pat ient. This Gly12Val variant is commonly seen as a somatic mutation in several ca ncers (Catalogue of Somatic Mutations in Cancer, http://www.sanger.ac.uk/cosmic) and functional studies have shown it to dramatically alter cell growth (Aoki 20 05). Therefore, this variant is highly likely to be pathogenic. - |
Epidermal nevus Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2012 | - - |
Malignant tumor of urinary bladder Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2012 | - - |
Melanoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 03, 2024 | Published functional studies demonstrate a slower activation rate and reduced catalytic activity (PMID: 23487764, 24224811); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34184824, 24224811, 22584058, 24057668, 23376849, 23093928, 22495892, 24803665, 27195699, 26325505, 28455154, 17412879, 30664540, 31974414, 29493581, 23487764) - |
Cardiovascular phenotype Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 25, 2023 | The c.35G>T (p.G12V) alteration is located in exon 2 (coding exon 1) of the HRAS gene. This alteration results from a G to T substitution at nucleotide position 35, causing the glycine (G) at amino acid position 12 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been observed or determined to be the result of a de novo mutation in multiple individuals with features consistent with HRAS-related RASopathy (Aoki, 2005; van der Burgt, 2007; Burkitt-Wright, 2012). Another alteration at the same codon, c.34G>A (p.G12S), was reported in multiple individuals with features consistent with HRAS-related RASopathy (Aoki, 2005). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. - |
Myopathy, congenital, with excess of muscle spindles Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2012 | - - |
HRAS-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 12, 2023 | The HRAS c.35G>T variant is predicted to result in the amino acid substitution p.Gly12Val. This variant has been reported as a recurrent de novo variant in multiple individuals with Costello syndrome (Patient 4, Burkitt-Wright et al 2012. PubMed ID: 22495892; van der Burgt et al 2007. PubMed ID: 17412879; Bend et al. 2019. PubMed ID: 30664540; Vora et al. 2020. PubMed ID: 31974414). Of note, >90% of pathogenic HRAS variants alter the conserved glycine residues at positions 12 and 13 (Aoki et al. 2005. PubMed ID: 16170316; Gripp et al. 2006. PubMed ID: 16329078; van der Burgt et al 2007. PubMed ID: 17412879). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. - |
Thyroid tumor Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Oct 02, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Pathogenic
.;D;.;D;D
Eigen
Uncertain
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;M
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D
Polyphen
P;P;P;P;P
Vest4
MutPred
Loss of ubiquitination at K16 (P = 0.1037);Loss of ubiquitination at K16 (P = 0.1037);Loss of ubiquitination at K16 (P = 0.1037);Loss of ubiquitination at K16 (P = 0.1037);Loss of ubiquitination at K16 (P = 0.1037);
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