chr10-43111500-C-T
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_020975.6(RET):c.1522+35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000092 in 1,597,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000091 ( 0 hom. )
Consequence
RET
NM_020975.6 intron
NM_020975.6 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.147
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 Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.93).
BP6
Variant 10-43111500-C-T is Benign according to our data. Variant chr10-43111500-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241337.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RET | NM_020975.6 | c.1522+35C>T | intron_variant | ENST00000355710.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RET | ENST00000355710.8 | c.1522+35C>T | intron_variant | 5 | NM_020975.6 | P4 |
Frequencies
GnomAD3 genomes AF: 0.000105 AC: 16AN: 152124Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.000111 AC: 25AN: 225766Hom.: 0 AF XY: 0.000105 AC XY: 13AN XY: 123834
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GnomAD4 exome AF: 0.0000906 AC: 131AN: 1445348Hom.: 0 Cov.: 34 AF XY: 0.000117 AC XY: 84AN XY: 716918
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GnomAD4 genome AF: 0.000105 AC: 16AN: 152124Hom.: 0 Cov.: 34 AF XY: 0.0000673 AC XY: 5AN XY: 74310
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 25, 2017 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This in an intronic variant at +35. It is classified in ClinVar as Likely benign by Invitae. It has a MaxMAF in ExAC of 0.05% (2 Finnish alleles and 14 non-Finnish European alleles). It has been reported in one individual with Hirschprung disease. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 22, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2021 | - - |
Multiple endocrine neoplasia type 2B Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Sep 27, 2016 | - - |
Multiple endocrine neoplasia type 2A Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Sep 27, 2016 | - - |
Multiple endocrine neoplasia, type 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Sep 25, 2022 | - - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 18, 2021 | - - |
RET-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 02, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Benign
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at