rs886037677
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_ModeratePM2PP3_ModeratePP5_Very_Strong
The NM_177438.3(DICER1):c.1752+1del variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
DICER1
NM_177438.3 splice_donor
NM_177438.3 splice_donor
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.88
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 14 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.041948345 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.9, offset of 0 (no position change), new splice context is: aaaGTaaga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 14-95116451-AC-A is Pathogenic according to our data. Variant chr14-95116451-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 254294.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.1752+1del | splice_donor_variant | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.1752+1del | splice_donor_variant | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
DICER1-related tumor predisposition Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 26, 2023 | This sequence change creates a premature translational stop signal (p.Ile585Serfs*2) in the DICER1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DICER1 are known to be pathogenic (PMID: 19556464, 21266384). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pleuropulmonary blastoma (PMID: 26925222). This variant is also known as c.1752+1del. ClinVar contains an entry for this variant (Variation ID: 254294). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
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, criteria provided, single submitter | clinical testing | International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota | Nov 10, 2014 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
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Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 3
DS_DL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at