rs886037729
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PP3PM2_SupportingPM1_SupportingPS4_ModeratePS3_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.5465A>T variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by valine at amino acid 1822 (p.Asp1822Val). This variant received a total of 3 phenotype points across 3 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 2-3.5 points (PMIDs: 26925222, 21266384) (PS4_Moderate). This variant is absent from gnomAD v2.1.1 and v.3.1.1 (PM2_Supporting). In vitro cleavage assay in HEK293 cells showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (Wu 2018, McGill University)(PS3_Supporting). This variant resides within the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PMID:31342592) (PM1_Supporting). The computational predictor REVEL gives a score of 0.954, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Moderate, PM1_Supporting, PM2_supporting, PS3_Supporting, PP3. (Bayesian Points: 6; VCEP specifications version 1; 02/11/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10586400/MONDO:0017288/024
Frequency
Consequence
NM_177438.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.5465A>T | p.Asp1822Val | missense_variant | 25/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.5465A>T | p.Asp1822Val | missense_variant | 25/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
DICER1-related tumor predisposition Pathogenic:3
Likely pathogenic, reviewed by expert panel | curation | ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen | May 18, 2022 | The NM_177438.2:c.5465A>T variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by valine at amino acid 1822 (p.Asp1822Val). This variant received a total of 3 phenotype points across 3 unrelated probands meeting DICER1 VCEP phenotype specificity scoring criteria of 2-3.5 points (PMIDs: 26925222, 21266384) (PS4_Moderate). This variant is absent from gnomAD v2.1.1 and v.3.1.1 (PM2_Supporting). In vitro cleavage assay in HEK293 cells showed that this variant reduces the capacity of the protein to produce 5p/3p microRNAs from a pre-miRNA, indicating that this variant impacts protein function (Wu 2018, McGill University)(PS3_Supporting). This variant resides within the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PMID: 31342592) (PM1_Supporting). The computational predictor REVEL gives a score of 0.954, which is above the threshold of 0.75, evidence that correlates with impact to DICER1 function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Moderate, PM1_Supporting, PM2_supporting, PS3_Supporting, PP3. (Bayesian Points: 6; VCEP specifications version 1; 02/11/2022) - |
Pathogenic, criteria provided, single submitter | clinical testing | International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota | Nov 10, 2014 | - - |
Likely pathogenic, criteria provided, single submitter | curation | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jul 01, 2019 | ACMG criteria met: PS3, PM1, PM2, PP4 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at