rs375689793

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_177438.3(DICER1):​c.589C>T​(p.Pro197Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,611,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

4
15

Clinical Significance

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

Conservation

PhyloP100: 4.09
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the DICER1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 111 curated benign missense variants. Gene score misZ: 4.2261 (above the threshold of 3.09). Trascript score misZ: 6.1353 (above the threshold of 3.09). GenCC associations: The gene is linked to goiter, multinodular 1, with or without Sertoli-Leydig cell tumors, global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome, DICER1-related tumor predisposition, DICER1 syndrome, pleuropulmonary blastoma.
BP4
Computational evidence support a benign effect (MetaRNN=0.1671241).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DICER1NM_177438.3 linkc.589C>T p.Pro197Ser missense_variant Exon 6 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.589C>T p.Pro197Ser missense_variant Exon 6 of 27 1 NM_177438.3 ENSP00000343745.3 Q9UPY3-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152136
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249166
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134940
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000886
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1459806
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726324
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152136
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74326
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000101
Hom.:
0
Bravo
AF:
0.0000189
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome Uncertain:1
Jul 11, 2023
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

DICER1-related tumor predisposition Uncertain:1
Oct 27, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 197 of the DICER1 protein (p.Pro197Ser). This variant is present in population databases (rs375689793, gnomAD 0.0009%). 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: 477274). 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 95%. 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
Oct 19, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.P197S variant (also known as c.589C>T), located in coding exon 5 of the DICER1 gene, results from a C to T substitution at nucleotide position 589. The proline at codon 197 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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
Benign
0.066
BayesDel_addAF
Benign
-0.22
T
BayesDel_noAF
Benign
-0.55
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.20
T;T;T;T;.
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.042
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.87
.;.;D;.;D
M_CAP
Benign
0.0087
T
MetaRNN
Benign
0.17
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.66
N;N;N;N;N
PrimateAI
Uncertain
0.53
T
PROVEAN
Benign
-0.22
N;N;N;N;N
REVEL
Benign
0.066
Sift
Benign
0.30
T;T;T;T;T
Sift4G
Benign
0.74
T;T;T;T;T
Polyphen
0.0070
B;B;B;B;.
Vest4
0.29
MVP
0.26
MPC
0.50
ClinPred
0.33
T
GERP RS
4.7
Varity_R
0.13
gMVP
0.30

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs375689793; hg19: chr14-95595954; API