rs1555369315
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_177438.3(DICER1):c.3952C>T(p.Leu1318Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
DICER1
NM_177438.3 missense
NM_177438.3 missense
Scores
11
6
1
Clinical Significance
Conservation
PhyloP100: 9.96
Genes affected
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, DICER1
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.946
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DICER1 | NM_177438.3 | c.3952C>T | p.Leu1318Phe | missense_variant | 21/27 | ENST00000343455.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DICER1 | ENST00000343455.8 | c.3952C>T | p.Leu1318Phe | missense_variant | 21/27 | 1 | NM_177438.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
DICER1-related tumor predisposition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1318 of the DICER1 protein (p.Leu1318Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 477171). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DICER1 protein function with a positive predictive value of 80%. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 26, 2023 | The p.L1318F variant (also known as c.3952C>T), located in coding exon 20 of the DICER1 gene, results from a C to T substitution at nucleotide position 3952. The leucine at codon 1318 is replaced by phenylalanine, an amino acid with highly similar properties. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;D;D;D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;M;.;M
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
N;N;N;N;N;N
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
P;P;P;P;.;.
Vest4
MutPred
Loss of stability (P = 0.1427);Loss of stability (P = 0.1427);Loss of stability (P = 0.1427);Loss of stability (P = 0.1427);.;Loss of stability (P = 0.1427);
MVP
MPC
1.5
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at