chr14-95115805-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_177438.3(DICER1):​c.1769G>T​(p.Cys590Phe) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C590S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

DICER1
NM_177438.3 missense

Scores

8
5
6

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.66

Publications

0 publications found
Variant links:
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]
DICER1 Gene-Disease associations (from GenCC):
  • DICER1-related tumor predisposition
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • pleuropulmonary blastoma
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • DICER1 syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome
    Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.779

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DICER1NM_177438.3 linkc.1769G>T p.Cys590Phe missense_variant Exon 11 of 27 ENST00000343455.8 NP_803187.1 Q9UPY3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DICER1ENST00000343455.8 linkc.1769G>T p.Cys590Phe missense_variant Exon 11 of 27 1 NM_177438.3 ENSP00000343745.3 Q9UPY3-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Feb 12, 2025
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

DICER1-related tumor predisposition Uncertain:1
Sep 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 590 of the DICER1 protein (p.Cys590Phe). 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: 483419). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DICER1 protein function with a negative 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
Jul 12, 2023
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.C590F variant (also known as c.1769G>T), located in coding exon 10 of the DICER1 gene, results from a G to T substitution at nucleotide position 1769. The cysteine at codon 590 is replaced by phenylalanine, an amino acid with highly dissimilar 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.70
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.82
D;D;D;D;.
Eigen
Benign
0.088
Eigen_PC
Uncertain
0.26
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.93
.;.;D;.;D
M_CAP
Benign
0.043
D
MetaRNN
Pathogenic
0.78
D;D;D;D;D
MetaSVM
Benign
-0.94
T
MutationAssessor
Benign
1.6
L;L;L;L;L
PhyloP100
7.7
PrimateAI
Pathogenic
0.80
T
PROVEAN
Pathogenic
-4.5
D;D;D;D;D
REVEL
Uncertain
0.35
Sift
Benign
0.043
D;D;D;D;D
Sift4G
Uncertain
0.015
D;D;D;D;D
Polyphen
0.13
B;B;B;B;.
Vest4
0.93
MutPred
0.30
Loss of methylation at K589 (P = 0.0427);Loss of methylation at K589 (P = 0.0427);Loss of methylation at K589 (P = 0.0427);Loss of methylation at K589 (P = 0.0427);Loss of methylation at K589 (P = 0.0427);
MVP
0.93
MPC
1.2
ClinPred
0.98
D
GERP RS
5.0
Varity_R
0.77
gMVP
0.84
Mutation Taster
=30/70
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs1555372646; hg19: chr14-95582142; API