rs121917758
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_005343.4(HRAS):c.173C>T(p.Thr58Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,978 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: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
HRAS
NM_005343.4 missense
NM_005343.4 missense
Scores
13
4
1
Clinical Significance
Conservation
PhyloP100: 9.80
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]
LRRC56 (HGNC:25430): (leucine rich repeat containing 56) Predicted to be involved in cell projection organization. Predicted to be located in cilium. Implicated in primary ciliary dyskinesia 39. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PM1
In a chain GTPase HRas (size 185) 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;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99
PP5
Variant 11-533883-G-A is Pathogenic according to our data. Variant chr11-533883-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12610.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr11-533883-G-A is described in UniProt as null. Variant chr11-533883-G-A is described in UniProt as null. Variant chr11-533883-G-A is described in UniProt as null.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| HRAS | ENST00000311189.8 | c.173C>T | p.Thr58Ile | missense_variant | Exon 3 of 6 | 1 | NM_005343.4 | ENSP00000309845.7 | ||
| HRAS | ENST00000417302.7 | c.173C>T | p.Thr58Ile | missense_variant | Exon 3 of 6 | 5 | NM_176795.5 | ENSP00000388246.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1460978Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 726812
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34
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Costello syndrome Pathogenic:7
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 23, 2014 | The Thr58Ile variant in HRAS has been reported in three individuals with clinica l features of Costello syndrome (Gripp 2008, Gripp 2012, LMM unpublished data). It was identified to occur de novo in two of these individuals and segregated w ith disease in one affected relative from one of these families. This variant wa s absent from large population studies. Computational prediction tools and conse rvation analysis suggest that this variant may impact the protein, though this i nformation is not predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partner s.org/LMM). - |
| Pathogenic, no assertion criteria provided | clinical testing | Blueprint Genetics | Feb 03, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 24, 2024 | This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 58 of the HRAS protein (p.Thr58Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Costello syndrome (PMID: 18247425, 22488832, 26888048). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12610). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is expected to disrupt HRAS function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 15, 2008 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jun 12, 2020 | PS1, PS4_supporting, PM1, PM2, PP5 The HRAS c.173C>T variant is a single nucleotide change from a cytosine to a thymine at position 173 which is predicted to substitute the amino acid threonine at position 58 in the protein to isoleucine. The variant is located in exon 3. This variant has been reported in the literature in patients with Costello syndrome, and this particular variant appears to be associated with an attenuated phenotype and has been described in a father and son (PMID: 22488832; PMID: 18247425) (PS4_supporting). The variant is in dbSNP (rs121917758) but is absent from population databases (PM2). This variant has been classified by the ClinGen RASopathy Variant Curation Expert Panel as Pathogenic and is reported as Pathogenic in the ClinVar database (Variation ID: 12610) (PP5). This variant was detected in both the affected child and her mother. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | Sep 02, 2022 | 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 (GeneReviews).(I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to isoleucine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (1 heterozygote, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants in the Ras domain (Decipher; PMID 29493581). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as de novo in at least two individuals with Costello syndrome (PMID 18247425; PMID 26888048). It has also been reported in a father and child with an attenuated Costello syndrome phenotype (PMID 22488832). This variant has been classified as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (ClinVar). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
| Pathogenic, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 03, 2017 | The c.173C>T (p.Thr58Ile) variant in HRAS has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; PMID 20112233, 16474405). Also, at least 2 independent occurrences of this variant have been detected in patients with a RASopathy (PS4_Supporting; PMID: 22488832, 18247425, 23321623, 20949621, 16921267). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The p.Thr58Ile variant in HRAS is analogous to the same previously established amino acid change in the KRAS gene and the ClinGen RASopathy Expert Panel has defined that the pathogenicities of analogous variants in the HRAS and KRAS genes are correlated based on the assumption that a known functional residue in one gene is equivalent to other functions within that subgroup (PS1; 29493581). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of HRAS (PM1; PMID 29493581). The variant is in HRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with low rate of benign missense with missense variants commonly being pathogenic (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr58Ile variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6, PS4_Supporting, PM2, PS1, PM1, PP2, PP3. - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2024 | HRAS: PS2, PM1, PM2, PS4:Moderate, PP3 - |
HRAS-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 06, 2024 | The HRAS c.173C>T variant is predicted to result in the amino acid substitution p.Thr58Ile. This variant has been repeatedly confirmed de novo in individuals with clinical features of Costello syndrome (Gripp et al. 2008. PubMed ID: 18247425; Gripp et al. 2012. PubMed ID: 22488832; Hiippala et al. 2016. PubMed ID: 26888048). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been interpreted as pathogenic by the ClinGen RASopathy Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/12610/). This variant is interpreted as pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
.;D;.;D;D
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;M;M;M
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
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 glycosylation at T58 (P = 0.0515);Loss of glycosylation at T58 (P = 0.0515);Loss of glycosylation at T58 (P = 0.0515);Loss of glycosylation at T58 (P = 0.0515);Loss of glycosylation at T58 (P = 0.0515);
MVP
MPC
2.2
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