chr14-95104123-G-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_177438.3(DICER1):​c.3273C>A​(p.Tyr1091*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y1091Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

DICER1
NM_177438.3 stop_gained

Scores

3
3
1

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.68

Publications

0 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 10 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;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DICER1NM_177438.3 linkc.3273C>A p.Tyr1091* stop_gained Exon 21 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.3273C>A p.Tyr1091* stop_gained Exon 21 of 27 1 NM_177438.3 ENSP00000343745.3 Q9UPY3-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459008
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
725992
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00
AC:
0
AN:
33454
American (AMR)
AF:
0.00
AC:
0
AN:
44694
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26118
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39682
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86088
European-Finnish (FIN)
AF:
0.0000385
AC:
2
AN:
51906
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5480
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1111274
Other (OTH)
AF:
0.00
AC:
0
AN:
60312
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.225
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
36
DANN
Uncertain
1.0
Eigen
Pathogenic
0.69
Eigen_PC
Uncertain
0.55
FATHMM_MKL
Uncertain
0.96
D
PhyloP100
1.7
Vest4
0.97
GERP RS
3.8
Mutation Taster
=0/200
disease causing (fs/PTC)

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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: rs886037698; hg19: chr14-95570460; API