rs369465519
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS3_SupportingBS2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.4740G>T variant in DICER1 is a missense variant predicted to cause substitution of glutamine by histidine at amino acid 1580 (p.Gln1580His). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors/GTRs: 500031, 61756). The highest population minor allele frequency in gnomAD (non-cancer) v2.1.1 is 0.00003 (3/102668 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In vitro cleavage assay in HEK293 cells showed that this variant produces both 5p and 3p microRNAs from a pre-miRNA, indicating that this variant is unlikely to impact protein function (BS3_Supporting; Wu 2018, McGill University). The computational predictor REVEL gives a score of 0.696, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function. In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BS3_Supporting. (Bayesian Points: -2; VCEP specifications version 1.1.0; 10/25/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA7330808/MONDO:0017288/024
Frequency
Consequence
NM_177438.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.4740G>T | p.Gln1580His | missense_variant | 23/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.4740G>T | p.Gln1580His | missense_variant | 23/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251382Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135862
GnomAD4 exome AF: 0.0000486 AC: 71AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37AN XY: 727242
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74378
ClinVar
Submissions by phenotype
DICER1-related tumor predisposition Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | - - |
Likely benign, reviewed by expert panel | curation | ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen | Oct 25, 2022 | The NM_177438.2:c.4740G>T variant in DICER1 is a missense variant predicted to cause substitution of glutamine by histidine at amino acid 1580 (p.Gln1580His). This variant has been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors/GTRs: 500031, 61756). The highest population minor allele frequency in gnomAD (non-cancer) v2.1.1 is 0.00003 (3/102668 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In vitro cleavage assay in HEK293 cells showed that this variant produces both 5p and 3p microRNAs from a pre-miRNA, indicating that this variant is unlikely to impact protein function (BS3_Supporting; Wu 2018, McGill University). The computational predictor REVEL gives a score of 0.696, which is neither above nor below the thresholds predicting a damaging or benign impact on DICER1 function. In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BS3_Supporting. (Bayesian Points: -2; VCEP specifications version 1.1.0; 10/25/2022) - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a seminoma (Slade 2011); This variant is associated with the following publications: (PMID: 24136150, 21266384, 24708902, 23547758, 33158809, 29762508, 28748527) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 14, 2023 | The p.Q1580H variant (also known as c.4740G>T), located in coding exon 22 of the DICER1 gene, results from a G to T substitution at nucleotide position 4740. The glutamine at codon 1580 is replaced by histidine, an amino acid with highly similar properties. This alteration was reported in the germline of an individual with a seminoma diagnosed at age 32 (Slade I et al. J. Med. Genet., 2011 Apr;48:273-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | curation | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Jul 01, 2019 | ACMG criteria met: PP3, BS3, BP1 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at