rs886037674
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_177438.3(DICER1):c.1684_1685del(p.Met562ValfsTer11) 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: 9.29
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 14-95116519-CAT-C is Pathogenic according to our data. Variant chr14-95116519-CAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 254290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95116519-CAT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.1684_1685del | p.Met562ValfsTer11 | frameshift_variant | 10/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.1684_1685del | p.Met562ValfsTer11 | frameshift_variant | 10/27 | 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:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
DICER1-related tumor predisposition Pathogenic:3
Pathogenic, criteria provided, single submitter | curation | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jul 01, 2019 | ACMG criteria met: PVS1, PM2, PM7, PP4 - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 09, 2018 | Loss-of-function variants in DICER1 are known to be pathogenic (PMID: 19556464, 21266384). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in several individuals affected with pleuropulmonary blastoma (PMID: 19556464, 26925222). ClinVar contains an entry for this variant (Variation ID: 254290). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Met562Valfs*11) in the DICER1 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota | Nov 10, 2014 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 01, 2021 | The c.1684_1685delAT pathogenic mutation, located in coding exon 9 of the DICER1 gene, results from a deletion of two nucleotides at nucleotide positions 1684 to 1685, causing a translational frameshift with a predicted alternate stop codon (p.M562Vfs*11). This mutation has been reported in multiple patients with pleuropulmonary blastoma (Hill DA et al. Science, 2009 Aug;325:965; Brenneman M et al. F1000Res, 2015 Jul;4:214). Of note, this alteration is also referred to as 1866-1867delAT in the literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
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