rs1800859
Variant summary
Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2
The NM_020975.6(RET):c.375C>A(p.Val125=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,614,248 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0085 ( 10 hom., cov: 33)
Exomes 𝑓: 0.010 ( 105 hom. )
Consequence
RET
NM_020975.6 synonymous
NM_020975.6 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.206
Genes affected
RET (HGNC:9967): (ret proto-oncogene) This gene encodes a transmembrane receptor and member of the tyrosine protein kinase family of proteins. Binding of ligands such as GDNF (glial cell-line derived neurotrophic factor) and other related proteins to the encoded receptor stimulates receptor dimerization and activation of downstream signaling pathways that play a role in cell differentiation, growth, migration and survival. The encoded receptor is important in development of the nervous system, and the development of organs and tissues derived from the neural crest. This proto-oncogene can undergo oncogenic activation through both cytogenetic rearrangement and activating point mutations. Mutations in this gene are associated with Hirschsprung disease and central hypoventilation syndrome and have been identified in patients with renal agenesis. [provided by RefSeq, Sep 2017]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -12 ACMG points.
BP6
Variant 10-43102379-C-A is Benign according to our data. Variant chr10-43102379-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 95997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-43102379-C-A is described in Lovd as [Benign].
BS2
High Homozygotes in GnomAd4 at 10 AD,AR gene
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RET | NM_020975.6 | c.375C>A | p.Val125= | synonymous_variant | 3/20 | ENST00000355710.8 | NP_066124.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RET | ENST00000355710.8 | c.375C>A | p.Val125= | synonymous_variant | 3/20 | 5 | NM_020975.6 | ENSP00000347942 | P4 |
Frequencies
GnomAD3 genomes 0.00846 AC: 1288AN: 152252Hom.: 10 Cov.: 33
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GnomAD3 exomes AF: 0.00736 AC: 1850AN: 251300Hom.: 15 AF XY: 0.00732 AC XY: 995AN XY: 135860
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GnomAD4 exome AF: 0.0104 AC: 15137AN: 1461878Hom.: 105 Cov.: 32 AF XY: 0.0102 AC XY: 7438AN XY: 727240
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GnomAD4 genome 0.00845 AC: 1288AN: 152370Hom.: 10 Cov.: 33 AF XY: 0.00806 AC XY: 601AN XY: 74522
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:21
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:8
| Benign, criteria provided, single submitter | clinical testing | GeneDx | May 08, 2015 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
| Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 20, 2012 | - - |
| Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
| Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
| Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 21, 2013 | Val125Val in exon 3 of RET: This variant is not expected to have clinical signif icance because it does not alter an amino acid residue and is not located within the splice consensus sequence. It has been identified in 1.2% (102/8600) of Eur opean American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS; dbSNP rs1800859). - |
not provided Benign:4
| Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2024 | RET: BS1, BS2 - |
| Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Oct 19, 2017 | - - |
| Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 07, 2023 | - - |
| Likely benign, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Multiple endocrine neoplasia, type 2 Benign:2
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
| Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 20, 2022 | - - |
Multiple endocrine neoplasia type 2B Benign:1
| Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Pheochromocytoma Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Aganglionic megacolon Benign:1
| Benign, no assertion criteria provided | research | Human Genomics Unit, Institute for molecular medicine Finland (FIMM) | Jan 01, 2013 | - - |
Renal hypodysplasia/aplasia 1 Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. - |
Hirschsprung disease, susceptibility to, 1 Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Multiple endocrine neoplasia Benign:1
| Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Hereditary cancer-predisposing syndrome Benign:1
| Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 25, 2014 | This alteration is classified as 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. - |
Computational scores
Source:
Name
Calibrated prediction
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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
DS_DG_spliceai
Position offset: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at