chr14-95096116-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 1P and 11B. PP2BP4_ModerateBP6BS1BS2

The NM_177438.3(DICER1):​c.4804G>A​(p.Ala1602Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000135 in 1,614,064 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: 𝑓 0.00012 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

19

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 1.87
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 -10 ACMG points.

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=0.069393545).
BP6
Variant 14-95096116-C-T is Benign according to our data. Variant chr14-95096116-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 412054.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.
BS1
Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000118 (18/152172) while in subpopulation SAS AF= 0.000414 (2/4830). AF 95% confidence interval is 0.0000729. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DICER1NM_177438.3 linkc.4804G>A p.Ala1602Thr 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.4804G>A p.Ala1602Thr missense_variant Exon 23 of 27 1 NM_177438.3 ENSP00000343745.3 Q9UPY3-1

Frequencies

GnomAD3 genomes
AF:
0.000118
AC:
18
AN:
152172
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000196
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000955
AC:
24
AN:
251372
Hom.:
0
AF XY:
0.000103
AC XY:
14
AN XY:
135850
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000653
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000150
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.000137
AC:
200
AN:
1461892
Hom.:
0
Cov.:
32
AF XY:
0.000142
AC XY:
103
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000896
Gnomad4 AMR exome
AF:
0.0000894
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000128
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000158
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
AF:
0.000118
AC:
18
AN:
152172
Hom.:
0
Cov.:
33
AF XY:
0.000134
AC XY:
10
AN XY:
74352
show subpopulations
Gnomad4 AFR
AF:
0.0000966
Gnomad4 AMR
AF:
0.000196
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000902
Hom.:
0
Bravo
AF:
0.000117
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000123
AC:
15
EpiCase
AF:
0.000109
EpiControl
AF:
0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

DICER1-related tumor predisposition Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 16, 2025- -
Uncertain significance, criteria provided, single submitterclinical testingSt. Jude Molecular Pathology, St. Jude Children's Research HospitalJun 17, 2021The DICER1 c.4804G>A (p.Ala1602Thr) missense change has a maximum subpopulation frequency of 0.016% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/14-95562453-C-T?dataset=gnomad_r2_1). Five of seven in silico tools predict a benign effect of this variant on protein function (BP4), but to our knowledge these predictions have not been confirmed by functional assays. Although this variant occurs in a gene where missense variants are more likely to be damaging (PMID: 27535533), the variant lies at a residue that has a constrained coding region score of 0 and is not predicted to be more damaging based on methods described by Havrilla et al (PMID: 30531870). This variant was identified in 1/1358 non-cancer control individuals in a study of individuals with multiple primary cancers (PMID: 29641532). To our knowledge, this variant has not been reported in individuals with DICER1 syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BP4. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Jan 02, 2022- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsApr 19, 2024This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalMar 04, 2025- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.065
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
16
DANN
Benign
0.88
DEOGEN2
Benign
0.20
T;T;T;T;.;.
Eigen
Benign
-0.16
Eigen_PC
Benign
-0.072
FATHMM_MKL
Benign
0.69
D
LIST_S2
Benign
0.77
.;.;T;.;T;T
M_CAP
Benign
0.0077
T
MetaRNN
Benign
0.069
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.97
L;L;L;L;.;L
PrimateAI
Benign
0.29
T
PROVEAN
Benign
0.56
N;N;N;N;N;N
REVEL
Benign
0.039
Sift
Benign
0.52
T;T;T;T;T;T
Sift4G
Benign
0.59
T;T;T;T;T;T
Polyphen
0.0
B;B;B;B;.;.
Vest4
0.097
MVP
0.66
MPC
0.47
ClinPred
0.023
T
GERP RS
3.2
Varity_R
0.061
gMVP
0.19

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: rs145669719; hg19: chr14-95562453; API