rs139786661
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_177438.3(DICER1):c.3428T>C(p.Leu1143Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,614,202 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1143I) has been classified as Uncertain significance.
Frequency
Consequence
NM_177438.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.3428T>C | p.Leu1143Pro | missense_variant | 21/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.3428T>C | p.Leu1143Pro | missense_variant | 21/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000677 AC: 103AN: 152208Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000171 AC: 43AN: 250930Hom.: 0 AF XY: 0.0000958 AC XY: 13AN XY: 135748
GnomAD4 exome AF: 0.0000828 AC: 121AN: 1461876Hom.: 0 Cov.: 32 AF XY: 0.0000743 AC XY: 54AN XY: 727238
GnomAD4 genome ? AF: 0.000689 AC: 105AN: 152326Hom.: 0 Cov.: 33 AF XY: 0.000685 AC XY: 51AN XY: 74476
ClinVar
Submissions by phenotype
not provided Benign:3
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 08, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 07, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Apr 28, 2022 | See Variant Classification Assertion Criteria. - |
DICER1-related tumor predisposition Benign:3
Likely benign, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Sep 10, 2020 | The c.3428T>C (p.Leu1143Pro) missense variant has a frequency of 0.0002586 (73 of 282,336 alleles) in gnomAD v2.1.1 with a maximum allele frequency of 0.002904 (72 of 24,794) in the African subpopulation (http://gnomad.broadinstitute.org). This is greater than the expected prevalence of a DICER1 pathogenic variant (BS1, PMID: 24761742). DICER1 has a missense z-score of >3.09 which suggests that this gene has a low rate of benign missense variation and that missense variants are more likely to be damaging (PP2). However, five of seven in silico tools predict a benign effect of this variant on protein function (BP4). This variant has been reported somatically in a case of pediatric acute myeloid leukemia (PMID: 29227476), but to our knowledge, this variant has not been reported in individuals with a personal or family history suggestive of DICER1 Tumor Predisposition syndrome (internal data and literature review). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria: BS1, BP4, PP2. - |
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.3428T>C variant in DICER1 is a missense variant predicted to cause substitution of leucine by proline at amino acid 1143 (p.Leu1143Pro). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; GTRs: 500031, 61756). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0029 (69/23442 alleles; FAF=0.0020) in African/African-American population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.102, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate 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 BENIGN for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2, BS1, BP4. (Bayesian Points: -9; VCEP specifications version 1; 02/11/2022) - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 22, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 14, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 28, 2019 | 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. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
DICER1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 22, 2021 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at