chr14-95108325-T-G

Variant summary

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

The NM_177438.3(DICER1):​c.2435A>C​(p.Gln812Pro) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

DICER1
NM_177438.3 missense, splice_region

Scores

1
14
4
Splicing: ADA: 0.9791
2

Clinical Significance

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

Conservation

PhyloP100: 3.66
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 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). 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DICER1NM_177438.3 linkc.2435A>C p.Gln812Pro missense_variant, splice_region_variant 15/27 ENST00000343455.8 NP_803187.1 Q9UPY3-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DICER1ENST00000343455.8 linkc.2435A>C p.Gln812Pro missense_variant, splice_region_variant 15/271 NM_177438.3 ENSP00000343745.3 Q9UPY3-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251244
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135782
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:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
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
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsDec 12, 2023- -
DICER1-related tumor predisposition Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 21, 2024This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 812 of the DICER1 protein (p.Gln812Pro). This variant is present in population databases (rs750049051, 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: 653119). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 15, 2024The p.Q812P variant (also known as c.2435A>C), located in coding exon 14 of the DICER1 gene, results from an A to C substitution at nucleotide position 2435. The glutamine at codon 812 is replaced by proline, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Uncertain
0.030
CADD
Pathogenic
28
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.69
D;D;D;D;.
Eigen
Uncertain
0.36
Eigen_PC
Uncertain
0.42
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.92
.;.;D;.;D
M_CAP
Uncertain
0.10
D
MetaRNN
Uncertain
0.46
T;T;T;T;T
MetaSVM
Benign
-0.40
T
MutationAssessor
Benign
1.5
L;L;L;L;L
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-2.6
D;D;D;D;D
REVEL
Uncertain
0.50
Sift
Uncertain
0.015
D;D;D;D;D
Sift4G
Uncertain
0.016
D;D;D;D;D
Polyphen
0.98
D;D;D;D;.
Vest4
0.55
MutPred
0.47
Gain of catalytic residue at P811 (P = 0.129);Gain of catalytic residue at P811 (P = 0.129);Gain of catalytic residue at P811 (P = 0.129);Gain of catalytic residue at P811 (P = 0.129);Gain of catalytic residue at P811 (P = 0.129);
MVP
0.89
MPC
1.2
ClinPred
0.88
D
GERP RS
5.7
Varity_R
0.88
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.98
dbscSNV1_RF
Pathogenic
0.92
SpliceAI score (max)
0.020
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: rs750049051; hg19: chr14-95574662; API