Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_177438.3(DICER1):c.2437-4T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
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]
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
?
BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 14-95108097-A-G is Benign according to our data. Variant chr14-95108097-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 412130.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
Uncertain significance, criteria provided, single submitter
clinical testing
Invitae
Sep 01, 2019
This sequence change falls in intron 15 of the DICER1 mRNA. It does not directly change the encoded amino acid sequence of the DICER1 protein. In summary, this is a novel intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this intronic variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DICER1-related disease. -
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter
clinical testing
Ambry Genetics
May 24, 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. -