rs148955573

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_177438.3(DICER1):ā€‹c.4805C>Gā€‹(p.Ala1602Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000149 in 1,614,206 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: š‘“ 0.000053 ( 0 hom., cov: 33)
Exomes š‘“: 0.000011 ( 0 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:2

Conservation

PhyloP100: 3.79
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 Benign. Variant got -12 ACMG points.

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.
BP4
Computational evidence support a benign effect (MetaRNN=0.054354936).
BP6
Variant 14-95096115-G-C is Benign according to our data. Variant chr14-95096115-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 479635.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS1
Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000109 (16/1461890) while in subpopulation AFR AF= 0.000418 (14/33480). AF 95% confidence interval is 0.000252. There are 0 homozygotes in gnomad4_exome. There are 7 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DICER1NM_177438.3 linkuse as main transcriptc.4805C>G p.Ala1602Gly missense_variant 23/27 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.4805C>G p.Ala1602Gly missense_variant 23/271 NM_177438.3 ENSP00000343745.3 Q9UPY3-1

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152198
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000169
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.0000318
AC:
8
AN:
251376
Hom.:
0
AF XY:
0.0000294
AC XY:
4
AN XY:
135854
show subpopulations
Gnomad AFR exome
AF:
0.000492
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000109
AC:
16
AN:
1461890
Hom.:
0
Cov.:
32
AF XY:
0.00000963
AC XY:
7
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.000418
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:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152316
Hom.:
0
Cov.:
33
AF XY:
0.0000537
AC XY:
4
AN XY:
74476
show subpopulations
Gnomad4 AFR
AF:
0.000168
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000474
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000907
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 20, 2024The c.4805C>G (p.A1602G) alteration is located in exon 23 (coding exon 22) of the DICER1 gene. This alteration results from a C to G substitution at nucleotide position 4805, causing the alanine (A) at amino acid position 1602 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Jan 10, 2022- -
DICER1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 25, 2023This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
DICER1-related tumor predisposition Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Benign
-0.30
T
BayesDel_noAF
Benign
-0.33
CADD
Benign
18
DANN
Benign
0.92
DEOGEN2
Benign
0.26
T;T;T;T;.;.
Eigen
Benign
-0.45
Eigen_PC
Benign
-0.34
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.73
.;.;T;.;T;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.054
T;T;T;T;T;T
MetaSVM
Benign
-0.73
T
MutationAssessor
Benign
0.97
L;L;L;L;.;L
PrimateAI
Benign
0.29
T
PROVEAN
Benign
0.020
N;N;N;N;N;N
REVEL
Benign
0.10
Sift
Benign
0.33
T;T;T;T;T;T
Sift4G
Benign
0.38
T;T;T;T;T;T
Polyphen
0.0
B;B;B;B;.;.
Vest4
0.19
MVP
0.73
MPC
0.49
ClinPred
0.024
T
GERP RS
2.4
Varity_R
0.11
gMVP
0.21

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: rs148955573; hg19: chr14-95562452; API