NM_177438.3:c.5241G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_177438.3(DICER1):c.5241G>A(p.Ser1747Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,614,096 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S1747S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0057 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 8 hom. )

Consequence

DICER1
NM_177438.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.92

Publications

5 publications found

Variant links:

COSMIC-nc: COSV58616018

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)

DICER1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 14-95094011-C-T is Benign according to our data. Variant chr14-95094011-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 242133.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.92 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00565 (860/152212) while in subpopulation AFR AF = 0.019 (789/41544). AF 95% confidence interval is 0.0179. There are 3 homozygotes in GnomAd4. There are 399 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 860 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3 link	c.5241G>A	p.Ser1747Ser	synonymous_variant	Exon 24 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8 link	c.5241G>A	p.Ser1747Ser	synonymous_variant	Exon 24 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes

AF:

0.00565

AC:

860

AN:

152094

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0190

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00308

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00528

GnomAD2 exomes

AF:

0.00139

AC:

349

AN:

251458

AF XY:

0.00105

show subpopulations

Gnomad AFR exome

AF:

0.0175

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000149

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000636

AC:

930

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000573

AC XY:

417

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0192

AC:

642

AN:

33478

American (AMR)

AF:

0.00141

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000162

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000108

AC:

120

AN:

1112004

Other (OTH)

AF:

0.00144

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

123

184

246

307

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00565

AC:

860

AN:

152212

Hom.:

Cov.:

AF XY:

0.00536

AC XY:

399

AN XY:

74406

show subpopulations

African (AFR)

AF:

0.0190

AC:

789

AN:

41544

American (AMR)

AF:

0.00307

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000208

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

68014

Other (OTH)

AF:

0.00523

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

129

172

215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00212

Hom.:

Bravo

AF:

0.00638

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Oct 27, 2015

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 16, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Jul 09, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

Mar 20, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

DICER1-related tumor predisposition

Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Hereditary cancer-predisposing syndrome

Benign:2

Feb 07, 2017

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This 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.

May 30, 2021

Sema4, Sema4

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

Pleuropulmonary blastoma

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

4.3

(source)

DANN

Benign

0.60

PhyloP100

-1.9

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over