rs1554884966
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM4PP5_Moderate
The NM_005343.4(HRAS):c.206_207insGGAGTACAGCGCCATGCGGGA(p.Glu62_Arg68dup) variant causes a inframe insertion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
HRAS
NM_005343.4 inframe_insertion
NM_005343.4 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.10
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 Likely_pathogenic. Variant got 8 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_005343.4
PM2
?
Very rare variant in population databases, with high coverage;
PM4
?
Nonframeshift variant in NON repetitive region in NM_005343.4.
PP5
?
Variant 11-533849-G-GTCCCGCATGGCGCTGTACTCC is Pathogenic according to our data. Variant chr11-533849-G-GTCCCGCATGGCGCTGTACTCC is described in ClinVar as [Pathogenic]. Clinvar id is 462149.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HRAS | NM_005343.4 | c.206_207insGGAGTACAGCGCCATGCGGGA | p.Glu62_Arg68dup | inframe_insertion | 3/6 | ENST00000311189.8 | |
HRAS | NM_176795.5 | c.206_207insGGAGTACAGCGCCATGCGGGA | p.Glu62_Arg68dup | inframe_insertion | 3/6 | ENST00000417302.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HRAS | ENST00000311189.8 | c.206_207insGGAGTACAGCGCCATGCGGGA | p.Glu62_Arg68dup | inframe_insertion | 3/6 | 1 | NM_005343.4 | P1 | |
HRAS | ENST00000417302.7 | c.206_207insGGAGTACAGCGCCATGCGGGA | p.Glu62_Arg68dup | inframe_insertion | 3/6 | 5 | NM_176795.5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Costello syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This variant, c.186_206dup, results in the insertion of 7 amino acid(s) of the HRAS protein (p.Glu62_Arg68dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with clinical features of RASopathy (PMID: 32499600, 34618388; Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 462149). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects HRAS function (PMID: 32499600, 34618388). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at