rs145669719

Variant summary

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

The NM_177438.3(DICER1):​c.4804G>T​(p.Ala1602Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

DICER1
NM_177438.3 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.87
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=0.13537952).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DICER1NM_177438.3 linkc.4804G>T p.Ala1602Ser missense_variant Exon 23 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.4804G>T p.Ala1602Ser missense_variant Exon 23 of 27 1 NM_177438.3 ENSP00000343745.3 Q9UPY3-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

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

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 23, 2023The p.A1602S variant (also known as c.4804G>T), located in coding exon 22 of the DICER1 gene, results from a G to T substitution at nucleotide position 4804. The alanine at codon 1602 is replaced by serine, an amino acid with similar properties. This amino acid position is conserved. 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
0.073
BayesDel_addAF
Benign
-0.054
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
17
DANN
Benign
0.89
DEOGEN2
Benign
0.19
T;T;T;T;.;.
Eigen
Benign
-0.010
Eigen_PC
Benign
0.023
FATHMM_MKL
Uncertain
0.92
D
LIST_S2
Uncertain
0.86
.;.;D;.;D;D
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.14
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.77
N;N;N;N;.;N
PrimateAI
Benign
0.28
T
PROVEAN
Benign
0.25
N;N;N;N;N;N
REVEL
Benign
0.055
Sift
Benign
0.50
T;T;T;T;T;T
Sift4G
Benign
0.72
T;T;T;T;T;T
Polyphen
0.0050
B;B;B;B;.;.
Vest4
0.21
MutPred
0.29
Gain of phosphorylation at A1602 (P = 0.0311);Gain of phosphorylation at A1602 (P = 0.0311);Gain of phosphorylation at A1602 (P = 0.0311);Gain of phosphorylation at A1602 (P = 0.0311);.;Gain of phosphorylation at A1602 (P = 0.0311);
MVP
0.73
MPC
0.45
ClinPred
0.060
T
GERP RS
3.2
Varity_R
0.081
gMVP
0.19

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: rs145669719; hg19: chr14-95562453; API