chr11-534285-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_005343.4(HRAS):c.38G>A(p.Gly13Asp) variant causes a missense change. 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. G13C) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 34)
Consequence
HRAS
NM_005343.4 missense
NM_005343.4 missense
Scores
11
3
4
Clinical Significance
Conservation
PhyloP100: 6.08
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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain 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 chr11-534286-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 12606.Status of the report is reviewed_by_expert_panel, 3 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 11-534285-C-T is Pathogenic according to our data. Variant chr11-534285-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12604.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-534285-C-T is described in UniProt as null. Variant chr11-534285-C-T is described in UniProt as null. Variant chr11-534285-C-T is described in UniProt as null. Variant chr11-534285-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| HRAS | NM_005343.4 | c.38G>A | p.Gly13Asp | missense_variant | 2/6 | ENST00000311189.8 | |
| HRAS | NM_176795.5 | c.38G>A | p.Gly13Asp | missense_variant | 2/6 | ENST00000417302.7 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| HRAS | ENST00000311189.8 | c.38G>A | p.Gly13Asp | missense_variant | 2/6 | 1 | NM_005343.4 | P1 | |
| HRAS | ENST00000417302.7 | c.38G>A | p.Gly13Asp | missense_variant | 2/6 | 5 | NM_176795.5 |
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:14Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Costello syndrome Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Jul 17, 2023 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Costello syndrome (MIM#218040) (PMID: 31222966). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 20301680). (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and high conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar, and has been observed in individuals with Costello syndrome (PMID: 28371260). (SP) 1207 - Parental origin of the variant is unresolved. Duo analysis has shown that this variant is not maternally inherited; however, a sample from this individual's father has not been tested. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, criteria provided, single submitter | clinical testing | Molecular Diagnostics Lab, Nemours Children's Health, Delaware | Jun 04, 2014 | - - |
| Pathogenic, no assertion criteria provided | research | Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University | Apr 02, 2022 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2005 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 18, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 28, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 13 of the HRAS protein (p.Gly13Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Costello syndrome (PMID: 28371260). ClinVar contains an entry for this variant (Variation ID: 12604). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt HRAS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HRAS function (PMID: 21850009). This variant disrupts the p.Gly13 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16329078, 18042262, 21438134). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Provincial Medical Genetics Program of British Columbia, University of British Columbia | Jan 01, 2022 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 28, 2023 | Published functional studies demonstrate aberrant RAS pathway activity (Niihori et al., 2011; Wey et al., 2013); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24803665, 24224811, 23751039, 23093928, 23487764, 28371260, 28425981, 30050098, 29907801, 32732226, 33726816, 34958143, 34906519, 21850009, 16170316) - |
Non-immune hydrops fetalis Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Jun 18, 2020 | - - |
Malignant tumor of urinary bladder;C0334082:Epidermal nevus;C0587248:Costello syndrome;C1842036:Large congenital melanocytic nevus;C4225426:Thyroid cancer, nonmedullary, 2;C4552097:Linear nevus sebaceous syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 10, 2022 | - - |
Noonan syndrome and Noonan-related syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Dec 12, 2016 | - - |
HRAS-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 09, 2022 | The HRAS c.38G>A variant is predicted to result in the amino acid substitution p.Gly13Asp. This variant is reported to be causative for Costello syndrome (see for example - Aoki et al. 2005. PubMed ID: 16170316; Takahashi and Ohashi. 2013. PubMed ID: 23751039; Bertola et al. 2017. PubMed ID: 28371260). Additionally, multiple missense variants affecting this amino acid (p.Gly13Arg, p.Gly13Cys, p.Gly13Val) have been reported to be pathogenic (Human Gene Mutation Database). 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. - |
RASopathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 15, 2018 | Variant summary: The HRAS c.38G>A (p.Gly13Asp) variant involves the alteration of a highly conserved nucleotide. The variant is located within the GTP/Mg2+ binding site in the conserved domain of Ras GTPase. 4/5 in silico tools predict a damaging outcome for this variant and it was experimentally confirmed to cause activation of RAS in vitro. This variant is absent from control dataset of gnomAD (~276492 chrs tested), but was identified in several Costello patients as a de novo event (Aoki_2005; Schulz _2008). The Gly13 codon appears to be a mutational hotspot, as other alterations, such as G13V and G13C, have been reported in patients with Costello Syndrome. Taken together, this variant is classified as Pathogenic. - |
Neoplasm of the large intestine Other:1
| not provided, no classification provided | literature only | Database of Curated Mutations (DoCM) | Mar 10, 2016 | - - |
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
Benign
Eigen_PC
Benign
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
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
Benign
D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
B;B;B;B;B
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
1.9
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