14-95103558-T-C

Variant summary

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

The NM_177438.3(DICER1):ā€‹c.3838A>Gā€‹(p.Ser1280Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.667
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 gene, where missense usually causes diseases (based on misZ statistic), DICER1. . Gene score misZ: 4.2261 (greater than the threshold 3.09). Trascript score misZ: 6.1353 (greater than threshold 3.09). The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 111 curated benign missense variants. GenCC has associacion of the gene with 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=0.080048054).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DICER1NM_177438.3 linkc.3838A>G p.Ser1280Gly missense_variant 21/27 ENST00000343455.8 NP_803187.1 Q9UPY3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DICER1ENST00000343455.8 linkc.3838A>G p.Ser1280Gly missense_variant 21/271 NM_177438.3 ENSP00000343745.3 Q9UPY3-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251302
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135812
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:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461850
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
727232
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:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

DICER1-related tumor predisposition Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 17, 2021This sequence change replaces serine with glycine at codon 1280 of the DICER1 protein (p.Ser1280Gly). The serine residue is weakly conserved and there is a small physicochemical difference between serine and glycine. This variant is present in population databases (rs148696745, ExAC 0.001%). This variant has not been reported in the literature in individuals with DICER1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
15
DANN
Uncertain
0.98
DEOGEN2
Benign
0.32
T;T;T;T;.;.
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.30
FATHMM_MKL
Uncertain
0.79
D
LIST_S2
Benign
0.72
.;.;T;.;T;T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.080
T;T;T;T;T;T
MetaSVM
Benign
-0.78
T
MutationAssessor
Benign
0.90
L;L;L;L;.;L
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.89
N;N;N;N;N;N
REVEL
Benign
0.030
Sift
Benign
0.32
T;T;T;T;T;T
Sift4G
Benign
0.39
T;T;T;T;T;T
Polyphen
0.0
B;B;B;B;.;.
Vest4
0.26
MVP
0.70
MPC
0.45
ClinPred
0.031
T
GERP RS
3.1
Varity_R
0.094
gMVP
0.29

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

LitVar

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

Other links and lift over

dbSNP: rs148696745; hg19: chr14-95569895; API