Genetic Variant DICER1:p.Ser1747Ser (chr14-95094011-C-T) – ACMG Classification: Benign (-21 pts)

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177438.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DICER1	NM_177438.3	MANE Select	c.5241G>A	p.Ser1747Ser	synonymous	Exon 24 of 27	NP_803187.1	Q9UPY3-1
DICER1	NM_001271282.3		c.5241G>A	p.Ser1747Ser	synonymous	Exon 24 of 27	NP_001258211.1	Q9UPY3-1
DICER1	NM_001291628.2		c.5241G>A	p.Ser1747Ser	synonymous	Exon 24 of 27	NP_001278557.1	Q9UPY3-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DICER1	ENST00000343455.8	TSL:1 MANE Select	c.5241G>A	p.Ser1747Ser	synonymous	Exon 24 of 27	ENSP00000343745.3	Q9UPY3-1
DICER1	ENST00000393063.6	TSL:1	c.5241G>A	p.Ser1747Ser	synonymous	Exon 26 of 29	ENSP00000376783.1	Q9UPY3-1
DICER1	ENST00000527414.5	TSL:1	c.5241G>A	p.Ser1747Ser	synonymous	Exon 24 of 27	ENSP00000435681.1	Q9UPY3-1

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

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (4)

DICER1-related tumor predisposition (2)

Hereditary cancer-predisposing syndrome (2)

not provided (2)

Pleuropulmonary blastoma (1)

Computational scores

Source: dbNSFP v4.9

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over