dbSNP rs544960260: DICER1:p.Glu1420del (chr14-95096657-ATCC-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_177438.3(DICER1):c.4260_4262delGGA(p.Glu1420del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00174 in 1,612,370 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E1420E) has been classified as Likely benign. The gene DICER1 is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 3 hom. )

Consequence

DICER1
NM_177438.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11O:1

Conservation

PhyloP100: 4.95

Publications

2 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

new If you want to explore the variant's impact on the transcript NM_177438.3, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Specifications for DICER1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_177438.3

BP6

Variant 14-95096657-ATCC-A is Benign according to our data. Variant chr14-95096657-ATCC-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 133971.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00121 (184/152044) while in subpopulation NFE AF = 0.0024 (163/67950). AF 95% confidence interval is 0.0021. There are 1 homozygotes in GnomAd4. There are 81 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 184 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.4260_4262delGGA	p.Glu1420del	disruptive_inframe_deletion	Exon 23 of 27	NP_803187.1	Q9UPY3-1
DICER1	NM_001271282.3		c.4260_4262delGGA	p.Glu1420del	disruptive_inframe_deletion	Exon 23 of 27	NP_001258211.1	Q9UPY3-1
DICER1	NM_001291628.2		c.4260_4262delGGA	p.Glu1420del	disruptive_inframe_deletion	Exon 23 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.4260_4262delGGA	p.Glu1420del	disruptive_inframe_deletion	Exon 23 of 27	ENSP00000343745.3	Q9UPY3-1
DICER1	ENST00000393063.6	TSL:1	c.4260_4262delGGA	p.Glu1420del	disruptive_inframe_deletion	Exon 25 of 29	ENSP00000376783.1	Q9UPY3-1
DICER1	ENST00000527414.5	TSL:1	c.4260_4262delGGA	p.Glu1420del	disruptive_inframe_deletion	Exon 23 of 27	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

184

AN:

151926

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000328

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000623

Gnomad FIN

AF:

0.000378

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00240

Gnomad OTH

AF:

0.000960

GnomAD2 exomes

AF:

0.00121

AC:

299

AN:

246384

AF XY:

0.00134

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000175

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.00229

Gnomad OTH exome

AF:

0.000663

GnomAD4 exome

AF:

0.00179

AC:

2615

AN:

1460326

Hom.:

AF XY:

0.00177

AC XY:

1283

AN XY:

726468

show subpopulations

African (AFR)

AF:

0.000240

AC:

AN:

33386

American (AMR)

AF:

0.000247

AC:

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.000307

AC:

AN:

26082

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.000721

AC:

AN:

85964

European-Finnish (FIN)

AF:

0.000469

AC:

AN:

53326

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00216

AC:

2399

AN:

1111298

Other (OTH)

AF:

0.00169

AC:

102

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

135

271

406

542

677

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

176

264

352

440

<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:

0.00121

AC:

184

AN:

152044

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41478

American (AMR)

AF:

0.000327

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.000624

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000378

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00240

AC:

163

AN:

67950

Other (OTH)

AF:

0.000950

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00149

Hom.:

Bravo

AF:

0.000997

EpiCase

AF:

0.00142

EpiControl

AF:

0.00214

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

not specified (4)

DICER1-related tumor predisposition (2)

Hereditary cancer-predisposing syndrome (2)

Pleuropulmonary blastoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

4.9

Mutation Taster

=62/38

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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