14-95096462-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_177438.3(DICER1):​c.4458A>C​(p.Lys1486Asn) 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. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Consequence

DICER1
NM_177438.3 missense

Scores

5
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.791
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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=0.2676757).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DICER1NM_177438.3 linkc.4458A>C p.Lys1486Asn 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.4458A>C p.Lys1486Asn 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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.34
BayesDel_addAF
Benign
-0.0093
T
BayesDel_noAF
Benign
-0.25
CADD
Benign
7.6
DANN
Uncertain
1.0
DEOGEN2
Benign
0.28
T;T;T;T;.;.
Eigen
Benign
-0.47
Eigen_PC
Benign
-0.70
FATHMM_MKL
Benign
0.22
N
LIST_S2
Benign
0.81
.;.;T;.;T;T
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.27
T;T;T;T;T;T
MetaSVM
Uncertain
0.38
D
MutationAssessor
Benign
1.7
L;L;L;L;.;L
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-0.51
N;N;N;N;N;N
REVEL
Benign
0.27
Sift
Uncertain
0.019
D;D;D;D;D;D
Sift4G
Benign
0.49
T;T;T;T;T;T
Polyphen
1.0
D;D;D;D;.;.
Vest4
0.38
MutPred
0.40
Loss of methylation at K1486 (P = 0.0152);Loss of methylation at K1486 (P = 0.0152);Loss of methylation at K1486 (P = 0.0152);Loss of methylation at K1486 (P = 0.0152);.;Loss of methylation at K1486 (P = 0.0152);
MVP
0.89
MPC
0.61
ClinPred
0.94
D
GERP RS
-6.0
Varity_R
0.15
gMVP
0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-95562799; API