Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2
The NM_177438.3(DICER1):āc.4891T>Gā(p.Ser1631Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00257 in 1,614,238 control chromosomes in the GnomAD database, including 10 homozygotes. 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 Likely benign (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1631Y) has been classified as Uncertain significance.
DICER1 (HGNC:17098): (dicer 1, ribonuclease III) This gene encodes a protein possessing an RNA helicase motif containing a DEXH box in its amino terminus and an RNA motif in the carboxy terminus. The encoded protein functions as a ribonuclease and is required by the RNA interference and small temporal RNA (stRNA) pathways to produce the active small RNA component that represses gene expression. This protein also acts as a strong antiviral agent with activity against RNA viruses, including the Zika and SARS-CoV-2 viruses. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2021]
Missense variant where missense usually causes diseases, DICER1
BP4
Computational evidence support a benign effect (MetaRNN=0.004314959).
BP6
Variant 14-95096029-A-C is Benign according to our data. Variant chr14-95096029-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 221072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95096029-A-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00121 (185/152346) while in subpopulation NFE AF= 0.00234 (159/68026). AF 95% confidence interval is 0.00204. There are 1 homozygotes in gnomad4. There are 89 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
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Likely benign, criteria provided, single submitter
clinical testing
GeneDx
Feb 18, 2021
This variant is associated with the following publications: (PMID: 21266384, 27930734) -
Likely benign, no assertion criteria provided
clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht
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Likely benign, criteria provided, single submitter
clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Oct 02, 2023
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Likely benign, criteria provided, single submitter
clinical testing
CeGaT Center for Human Genetics Tuebingen
Apr 01, 2024
DICER1: PP2, BP4, BS1 -
Likely benign, no assertion criteria provided
clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center
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not specified Benign:2
Benign, criteria provided, single submitter
clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano
Aug 11, 2021
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Likely benign, criteria provided, single submitter
clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Aug 15, 2023
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DICER1-related tumor predisposition Benign:2
Likely benign, criteria provided, single submitter
clinical testing
Illumina Laboratory Services, Illumina
Apr 27, 2017
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter
clinical testing
Invitae
Feb 01, 2024
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Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter
curation
Sema4, Sema4
Jul 02, 2020
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Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
Nov 08, 2018
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. -
Likely benign, criteria provided, single submitter
clinical testing
Fulgent Genetics, Fulgent Genetics
Apr 03, 2022
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DICER1-related disorder Benign:1
Likely benign, criteria provided, single submitter
clinical testing
PreventionGenetics, part of Exact Sciences
Oct 21, 2019
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). -
Breast neoplasm Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Institute of Human Genetics, University of Leipzig Medical Center