Genetic Variant DICER1:p.Arg509Gly (chr14-95116680-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_177438.3(DICER1):c.1525C>G(p.Arg509Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R509Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.55

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

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
DICER1	NM_177438.3	MANE Select	c.1525C>G	p.Arg509Gly	missense	Exon 10 of 27	NP_803187.1
DICER1	NM_001271282.3		c.1525C>G	p.Arg509Gly	missense	Exon 10 of 27	NP_001258211.1
DICER1	NM_001291628.2		c.1525C>G	p.Arg509Gly	missense	Exon 10 of 27	NP_001278557.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DICER1	ENST00000343455.8	TSL:1 MANE Select	c.1525C>G	p.Arg509Gly	missense	Exon 10 of 27	ENSP00000343745.3
DICER1	ENST00000393063.6	TSL:1	c.1525C>G	p.Arg509Gly	missense	Exon 12 of 29	ENSP00000376783.1
DICER1	ENST00000527414.5	TSL:1	c.1525C>G	p.Arg509Gly	missense	Exon 10 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.96

MetaSVM

Uncertain

0.54

MutationAssessor

Uncertain

2.7

PhyloP100

5.6

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.1

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.91

MutPred

0.80

Loss of MoRF binding (P = 0.0371)

MVP

0.98

MPC

1.6

ClinPred

1.0

GERP RS

3.1

Varity_R

0.95

gMVP

0.90

Mutation Taster

=33/67

disease causing

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over