rs200945755
Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_005343.4(HRAS):c.369C>T(p.Arg123=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00007 in 1,613,848 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000068 ( 1 hom. )
Consequence
HRAS
NM_005343.4 synonymous
NM_005343.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.617
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 Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
?
Variant 11-533534-G-A is Benign according to our data. Variant chr11-533534-G-A is described in ClinVar as [Benign]. Clinvar id is 259747.Status of the report is reviewed_by_expert_panel, 3 stars.
BP7
?
Synonymous conserved (PhyloP=0.617 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000919 (14/152330) while in subpopulation EAS AF= 0.0025 (13/5192). AF 95% confidence interval is 0.00148. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HRAS | NM_005343.4 | c.369C>T | p.Arg123= | synonymous_variant | 4/6 | ENST00000311189.8 | |
HRAS | NM_176795.5 | c.369C>T | p.Arg123= | synonymous_variant | 4/6 | ENST00000417302.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HRAS | ENST00000311189.8 | c.369C>T | p.Arg123= | synonymous_variant | 4/6 | 1 | NM_005343.4 | P1 | |
HRAS | ENST00000417302.7 | c.369C>T | p.Arg123= | synonymous_variant | 4/6 | 5 | NM_176795.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000920 AC: 14AN: 152212Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000167 AC: 42AN: 251344Hom.: 0 AF XY: 0.000147 AC XY: 20AN XY: 135910
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GnomAD4 exome AF: 0.0000677 AC: 99AN: 1461518Hom.: 1 Cov.: 35 AF XY: 0.0000605 AC XY: 44AN XY: 727082
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ClinVar
Significance: Benign
Submissions summary: Benign:9
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | HRAS: BP4, BP7 - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 23, 2017 | Variant summary: The HRAS c.369C>T (p.Arg123Arg) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. It is 81 nucleotides upstream from exon-intron boundary. 2/5 splice prediction tools predict a creation of cryptic splice donor site. ESE finder predicts that this variant may affect binding of ESE site(s). However, these predictions have yet to be confirmed by functional studies. This variant was found in 13/120964 control chromosomes, exclusively observed in the East Asian subpopulation at a frequency of 0.001505 (13/8638). This frequency is about 602 times the estimated maximal expected allele frequency of a pathogenic HRAS variant (0.0000025), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, one clinical diagnostic laboratory has classified this variant as likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories. Taken together, this variant is classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 20, 2023 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Costello syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 13, 2022 | - - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 04, 2022 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Noonan syndrome and Noonan-related syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 01, 2018 | - - |
RASopathy Benign:1
Benign, reviewed by expert panel | curation | ClinGen RASopathy Variant Curation Expert Panel | Apr 18, 2017 | The filtering allele frequency of the c.369C>T (p.Arg123=) variant in the HRAS gene is 0.089% (13/8638) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at