rs759764582
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM2_SupportingBS3
This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.1907+3A>T variant in DICER1 is an intronic variant located in exon 11. The results from 2 in silico splicing predictors [MaxEntScan, SpliceAI] do not agree, supporting neither a deleterious nor benign impact on splicing. The variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with DICER1 syndrome. Sequencing of RNA from 3 patients showed that this variant does not affect splicing, indicating that this variant is unlikely to impact protein function (BS3; Internal contributor GTR: 61756). In summary, this variant meets the criteria to be classified as LIKELY BENIGN for DICER1 syndrome. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS3, PM2_Supporting. (Bayesian Points: -3; VCEP specifications version 1; 02/11/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA915946406/MONDO:0017288/024
Frequency
Consequence
NM_177438.3 splice_donor_region, intron
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.1907+3A>T | splice_donor_region_variant, intron_variant | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.1907+3A>T | splice_donor_region_variant, intron_variant | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461820Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727218
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
DICER1-related tumor predisposition Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 06, 2020 | This sequence change falls in intron 11 of the DICER1 gene. It does not directly change the encoded amino acid sequence of the DICER1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DICER1-related conditions. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Likely benign, reviewed by expert panel | curation | ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen | May 18, 2022 | The NM_177438.2:c.1907+3A>T variant in DICER1 is an intronic variant located in exon 11. The results from 2 in silico splicing predictors [MaxEntScan, SpliceAI] do not agree, supporting neither a deleterious nor benign impact on splicing. The variant is absent from gnomAD v2.1.1 and v3.1.1 (non-cancer) (PM2_Supporting). To our knowledge, this variant has not been reported in the literature in any individuals with DICER1 syndrome. Sequencing of RNA from 3 patients showed that this variant does not affect splicing, indicating that this variant is unlikely to impact protein function (BS3; Internal contributor GTR: 61756). In summary, this variant meets the criteria to be classified as LIKELY BENIGN for DICER1 syndrome. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS3, PM2_Supporting. (Bayesian Points: -3; VCEP specifications version 1; 02/11/2022) - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 07, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at