rs886037680
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_177438.3(DICER1):c.1880_1883del(p.Ile627ThrfsTer22) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
DICER1
NM_177438.3 frameshift
NM_177438.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.08
Genes affected
DICER1 (HGNC:17098): (dicer 1, ribonuclease III) This gene encodes a protein possessing an RNA helicase motif containing a DEXH box in its amino terminus and an RNA motif in the carboxy terminus. The encoded protein functions as a ribonuclease and is required by the RNA interference and small temporal RNA (stRNA) pathways to produce the active small RNA component that represses gene expression. This protein also acts as a strong antiviral agent with activity against RNA viruses, including the Zika and SARS-CoV-2 viruses. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2021]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 14-95115690-GTTGA-G is Pathogenic according to our data. Variant chr14-95115690-GTTGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 254298.Status of the report is reviewed_by_expert_panel, 3 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.1880_1883del | p.Ile627ThrfsTer22 | frameshift_variant | 11/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.1880_1883del | p.Ile627ThrfsTer22 | frameshift_variant | 11/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
DICER1-related tumor predisposition Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota | Nov 10, 2014 | - - |
Pathogenic, criteria provided, single submitter | curation | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jul 01, 2019 | ACMG criteria met: PVS1, PM2, PP4 - |
Pathogenic, reviewed by expert panel | curation | ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen | May 18, 2022 | NM_177438.2(DICER1):c.1880_1883del (p.Ile627fs) variant in DICER1 is a frameshift variant predicted to cause a premature stop codon in biologically relevant exon 11/27 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant received a total of 1 phenotype point across 1 unrelated probands/families meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMIDs 26925222, ClinVar SCVs: SCV000581520.4, SCV000571419.5). The variant has been reported to segregate with disease in multiple affected family members, with 3 meioses from 1 family (PP1; ClinVar SCVs: SCV000581520.4). This variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer)(PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PVS1, PS4_Supporting, PP1, PM2_Supporting (Bayesian Points: 11; VCEP specifications version 1; 02/11/2022). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 15, 2020 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 26925222) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 16, 2013 | ​The c.1880_1883delTCAA pathogenic mutation, located in coding exon 10 of the DICER1 gene, results from a deletion of 4 nucleotides between positions 1880 and 1883, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Computational scores
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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