GeneBe

rs886037700

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_177438.3(DICER1):​c.3300delA​(p.Lys1100AsnfsTer44) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

DICER1
NM_177438.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 0.394

Publications

1 publications found
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]
DICER1 Gene-Disease associations (from GenCC):
  • DICER1-related tumor predisposition
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • pleuropulmonary blastoma
    Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • DICER1 syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome
    Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 14-95104095-AT-A is Pathogenic according to our data. Variant chr14-95104095-AT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 254319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DICER1NM_177438.3 linkc.3300delA p.Lys1100AsnfsTer44 frameshift_variant Exon 21 of 27 ENST00000343455.8 NP_803187.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DICER1ENST00000343455.8 linkc.3300delA p.Lys1100AsnfsTer44 frameshift_variant Exon 21 of 27 1 NM_177438.3 ENSP00000343745.3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1461554
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727080
African (AFR)
AF:
0.00
AC:
0
AN:
33478
American (AMR)
AF:
0.00
AC:
0
AN:
44714
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26130
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86238
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53220
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5734
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111962
Other (OTH)
AF:
0.00
AC:
0
AN:
60380
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

DICER1-related tumor predisposition Pathogenic:2
Nov 10, 2014
International Pleuropulmonary Blastoma Registry, Children's Hospitals and Clinics of Minnesota
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Jul 01, 2019
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:curation

ACMG criteria met: PVS1, PM2, PP4

Hereditary cancer-predisposing syndrome Pathogenic:1
Jan 22, 2024
Ambry Genetics
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.3300delA pathogenic mutation, located in coding exon 20 of the DICER1 gene, results from a deletion of one nucleotide at nucleotide position 3300, causing a translational frameshift with a predicted alternate stop codon (p.K1100Nfs*44). This variant was reported in an individual with features consistent with DICER1-related tumor predisposition syndrome (Khan NE et al. Pediatr Nephrol, 2018 Dec;33:2281-2288). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.39
Mutation Taster
=1/199
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs886037700; hg19: chr14-95570432; API