rs886037686
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PS4_SupportingPM2_SupportingBP4PS2
This summary comes from the ClinGen Evidence Repository: The NM_177438.3(DICER1):c.2236A>G variant in DICER1 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 746 (p.Arg746Gly). This variant received a total of 1 phenotype point across 1 proband with pleuropulmonary blastoma, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID:26925222). This observation was as a de novo occurrence with constitutional mosaicism (PS2; PMIDs:26925222). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). The computational predictor REVEL gives a score of 0.409, which is below the threshold of 0.5, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PS2, PM2_Supporting, BP4. (Bayesian Points: 5; VCEP specifications version 1.2.0; 08/22/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA10586443/MONDO:0100216/024
Frequency
Consequence
NM_177438.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.2236A>G | p.Arg746Gly | missense_variant | 14/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.2236A>G | p.Arg746Gly | missense_variant | 14/27 | 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:1Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota | Nov 10, 2014 | - - |
Uncertain significance, reviewed by expert panel | curation | ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen | Aug 22, 2023 | The NM_177438.3(DICER1):c.2236A>G variant in DICER1 is a missense variant predicted to cause substitution of arginine by glycine at amino acid 746 (p.Arg746Gly). This variant received a total of 1 phenotype point across 1 proband with pleuropulmonary blastoma, meeting DICER1 VCEP phenotype specificity scoring criteria of 1-1.5 points (PS4_Supporting; PMID: 26925222). This observation was as a de novo occurrence with constitutional mosaicism (PS2; PMIDs:26925222). This variant is absent from gnomAD v2.1.1 and v3.1.2 (non-cancer) (PM2_Supporting). The computational predictor REVEL gives a score of 0.409, which is below the threshold of 0.5, and the splice site predictor SpliceAI indicates that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). In summary, this variant meets the criteria to be classified as Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PS4_Supporting, PS2, PM2_Supporting, BP4. (Bayesian Points: 5; VCEP specifications version 1.2.0; 08/22/2023) - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jul 01, 2019 | ACMG criteria met: PP3, PP4, BP1 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at