Genetic Variant DICER1:p.Pro645Pro (chr14-95113197-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_030621.4(DICER1):c.1935G>A(p.Pro645Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00994 in 1,613,518 control chromosomes in the GnomAD database, including 119 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. P645P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0093 ( 15 hom., cov: 33)

Exomes 𝑓: 0.010 ( 104 hom. )

Consequence

DICER1
NM_030621.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: -2.04

Publications

10 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)

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=-0.53).

BP6

Variant 14-95113197-C-T is Benign according to our data. Variant chr14-95113197-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 221180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.04 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00929 (1414/152246) while in subpopulation NFE AF = 0.0106 (724/68014). AF 95% confidence interval is 0.01. There are 15 homozygotes in GnomAd4. There are 775 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1414 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030621.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DICER1	NM_177438.3	MANE Select	c.1935G>A	p.Pro645Pro	synonymous	Exon 12 of 27	NP_803187.1
DICER1	NM_001271282.3		c.1935G>A	p.Pro645Pro	synonymous	Exon 12 of 27	NP_001258211.1
DICER1	NM_001291628.2		c.1935G>A	p.Pro645Pro	synonymous	Exon 12 of 27	NP_001278557.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DICER1	ENST00000343455.8	TSL:1 MANE Select	c.1935G>A	p.Pro645Pro	synonymous	Exon 12 of 27	ENSP00000343745.3
DICER1	ENST00000393063.6	TSL:1	c.1935G>A	p.Pro645Pro	synonymous	Exon 14 of 29	ENSP00000376783.1
DICER1	ENST00000527414.5	TSL:1	c.1935G>A	p.Pro645Pro	synonymous	Exon 12 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes

AF:

0.00930

AC:

1415

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.0252

Gnomad AMR

AF:

0.00569

Gnomad ASJ

AF:

0.0372

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.0311

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0106

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.0103

AC:

2577

AN:

251344

AF XY:

0.0104

show subpopulations

Gnomad AFR exome

AF:

0.00117

Gnomad AMR exome

AF:

0.00659

Gnomad ASJ exome

AF:

0.0331

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0265

Gnomad NFE exome

AF:

0.0112

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.0100

AC:

14619

AN:

1461272

Hom.:

104

Cov.:

AF XY:

0.00990

AC XY:

7196

AN XY:

726968

show subpopulations

African (AFR)

AF:

0.00123

AC:

AN:

33462

American (AMR)

AF:

0.00680

AC:

304

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0346

AC:

905

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00293

AC:

253

AN:

86250

European-Finnish (FIN)

AF:

0.0258

AC:

1379

AN:

53412

Middle Eastern (MID)

AF:

0.0166

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00990

AC:

11003

AN:

1111484

Other (OTH)

AF:

0.0106

AC:

638

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

714

1427

2141

2854

3568

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

388

776

1164

1552

1940

<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:

0.00929

AC:

1414

AN:

152246

Hom.:

Cov.:

AF XY:

0.0104

AC XY:

775

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00205

AC:

AN:

41546

American (AMR)

AF:

0.00569

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0372

AC:

129

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00228

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0311

AC:

329

AN:

10586

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0106

AC:

724

AN:

68014

Other (OTH)

AF:

0.00852

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0112

Hom.:

Bravo

AF:

0.00753

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0140

EpiControl

AF:

0.0147

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

DICER1-related tumor predisposition (3)

not provided (3)

Hereditary cancer-predisposing syndrome (1)

Pleuropulmonary blastoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

5.4

(source)

DANN

Benign

0.62

PhyloP100

-2.0

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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