rs1060503649

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_177438.3(DICER1):ā€‹c.2738A>Gā€‹(p.Lys913Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)

Consequence

DICER1
NM_177438.3 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.92
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 3 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). GenCC has associacion of 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DICER1NM_177438.3 linkuse as main transcriptc.2738A>G p.Lys913Arg missense_variant 17/27 ENST00000343455.8 NP_803187.1 Q9UPY3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DICER1ENST00000343455.8 linkuse as main transcriptc.2738A>G p.Lys913Arg missense_variant 17/271 NM_177438.3 ENSP00000343745.3 Q9UPY3-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152238
Hom.:
0
Cov.:
32
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:
0.0000941
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
32
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152238
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74384
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:
0.0000941
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

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 GeneticsFeb 23, 2018The p.K913R variant (also known as c.2738A>G), located in coding exon 16 of the DICER1 gene, results from an A to G substitution at nucleotide position 2738. The lysine at codon 913 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved through opossum but not in all 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
0.074
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.53
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.13
T;T;T;T;.
Eigen
Benign
-0.024
Eigen_PC
Benign
0.21
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.93
.;.;D;.;D
M_CAP
Benign
0.0091
T
MetaRNN
Benign
0.23
T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.34
N;N;N;N;N
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-0.61
N;N;N;N;N
REVEL
Benign
0.062
Sift
Benign
0.10
T;T;T;T;T
Sift4G
Benign
0.48
T;T;T;T;T
Polyphen
0.033
B;B;B;B;.
Vest4
0.23
MutPred
0.45
Gain of catalytic residue at K913 (P = 0.011);Gain of catalytic residue at K913 (P = 0.011);Gain of catalytic residue at K913 (P = 0.011);Gain of catalytic residue at K913 (P = 0.011);Gain of catalytic residue at K913 (P = 0.011);
MVP
0.43
MPC
0.56
ClinPred
0.74
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.24
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.49
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.49
Position offset: 0

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: rs1060503649; hg19: chr14-95574011; API