rs749900564
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. BP4PM1_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_177438.2: c.5171C>T variant in DICER1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 1724 (p.Pro1724Leu). The highest population minor allele frequency in gnomAD v4.0.0 is 0.00001872 (1/53418 alleles) in European (Finnish) population, followed by 0.00001159 (1/86256 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant resides within the RNase IIIb mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID:31342592). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.45; MaxEntScan and SpliceAI: no effect on splicing) (BP4). Due to conflicting evidence, this variant is classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.2.0; 01/09/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA390865284/MONDO:0017288/024
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
DICER1
NM_177438.3 missense
NM_177438.3 missense
Scores
4
10
5
Clinical Significance
Conservation
PhyloP100: 9.52
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 Uncertain_significance. Variant got 0 ACMG points.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
BP4
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461866Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727236
GnomAD4 exome
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6
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1461866
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33
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3
AN XY:
727236
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GnomAD4 genome
GnomAD4 genome
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32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:8
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
DICER1-related tumor predisposition Uncertain:3
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 07, 2020 | This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 09, 2023 | 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. 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 not expected to disrupt DICER1 protein function. ClinVar contains an entry for this variant (Variation ID: 690455). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1724 of the DICER1 protein (p.Pro1724Leu). - |
| Uncertain significance, reviewed by expert panel | curation | ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen | Jan 09, 2024 | The NM_177438.2: c.5171C>T variant in DICER1 is a missense variant predicted to cause substitution of proline by leucine at amino acid 1724 (p.Pro1724Leu). The highest population minor allele frequency in gnomAD v4.0.0 is 0.00001872 (1/53418 alleles) in European (Finnish) population, followed by 0.00001159 (1/86256 alleles) in South Asian population (PM2_Supporting, BS1, and BA1 are not met). This variant resides within the RNase IIIb mutational hotspot domain with critical functionality as defined by the ClinGen DICER1 VCEP (PM1_Supporting; PMID: 31342592). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.45; MaxEntScan and SpliceAI: no effect on splicing) (BP4). Due to conflicting evidence, this variant is classified as Uncertain Significance for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM1_Supporting, BP4. (Bayesian Points: 0; VCEP specifications version 1.2.0; 01/09/2024) - |
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 24, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Euthyroid goiter;C1266144:Pleuropulmonary blastoma;C1867234:Rhabdomyosarcoma, embryonal, 2;C4748924:Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 08, 2022 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 01, 2023 | The p.P1724L variant (also known as c.5171C>T), located in coding exon 23 of the DICER1 gene, results from a C to T substitution at nucleotide position 5171. The proline at codon 1724 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;D;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;.;D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;N;N;.;N
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T
Polyphen
D;D;D;D;.;.
Vest4
MutPred
Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);Loss of disorder (P = 0.021);.;Loss of disorder (P = 0.021);
MVP
MPC
2.5
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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