rs587778231

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2

The NM_030621.4(DICER1):c.4923T>G(p.Cys1641Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000427 in 1,614,132 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C1641Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00019 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

DICER1
NM_030621.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:1O:1

Conservation

PhyloP100: 0.601

Publications

1 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07664263).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00019 (29/152240) while in subpopulation AFR AF = 0.000675 (28/41470). AF 95% confidence interval is 0.000479. There are 1 homozygotes in GnomAd4. There are 16 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High AC in GnomAd4 at 29 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.4923T>G	p.Cys1641Trp	missense	Exon 23 of 27	NP_803187.1
DICER1	NM_001271282.3		c.4923T>G	p.Cys1641Trp	missense	Exon 23 of 27	NP_001258211.1
DICER1	NM_001291628.2		c.4923T>G	p.Cys1641Trp	missense	Exon 23 of 27	NP_001278557.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DICER1	ENST00000343455.8	TSL:1 MANE Select	c.4923T>G	p.Cys1641Trp	missense	Exon 23 of 27	ENSP00000343745.3
DICER1	ENST00000393063.6	TSL:1	c.4923T>G	p.Cys1641Trp	missense	Exon 25 of 29	ENSP00000376783.1
DICER1	ENST00000527414.5	TSL:1	c.4923T>G	p.Cys1641Trp	missense	Exon 23 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes

AF:

0.000190

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000675

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000398

AC:

AN:

251422

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000274

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33480

American (AMR)

AF:

0.0000894

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1112010

Other (OTH)

AF:

0.0000166

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000190

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.000675

AC:

AN:

41470

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5206

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

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:

0.000132

Hom.:

Bravo

AF:

0.000204

ExAC

AF:

0.0000494

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

DICER1-related disorder (1)

DICER1-related tumor predisposition (1)

Diffuse midline glioma, H3 K27-altered (1)

Euthyroid goiter;C1867234:Rhabdomyosarcoma, embryonal, 2;C3839822:DICER1-related tumor predisposition (1)

Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome (1)

Hereditary cancer-predisposing syndrome (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.25

CADD

Benign

5.6

(source)

DANN

Benign

0.81

DEOGEN2

Benign

0.18

Eigen

Benign

-0.71

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.053

LIST_S2

Benign

0.85

M_CAP

Benign

0.050

MetaRNN

Benign

0.077

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.085

PhyloP100

0.60

PrimateAI

Benign

0.45

PROVEAN

Benign

1.5

REVEL

Benign

0.22

Sift

Benign

0.18

Sift4G

Benign

0.18

Polyphen

0.0

Vest4

0.40

MVP

0.81

MPC

0.66

ClinPred

0.0076

GERP RS

-2.3

Varity_R

0.20

gMVP

0.65

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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