14-95113177-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The ENST00000343455.8(DICER1):c.1955A>C(p.Lys652Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000806 in 1,613,616 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K652E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

DICER1
ENST00000343455.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 7.28

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP6

Variant 14-95113177-T-G is Benign according to our data. Variant chr14-95113177-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 477076.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.00000753 (11/1461410) while in subpopulation AMR AF = 0.000246 (11/44724). AF 95% confidence interval is 0.000137. There are 0 homozygotes in GnomAdExome4. There are 7 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 11 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000343455.8. 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.1955A>C	p.Lys652Thr	missense	Exon 12 of 27	NP_803187.1
DICER1	NM_001271282.3		c.1955A>C	p.Lys652Thr	missense	Exon 12 of 27	NP_001258211.1
DICER1	NM_001291628.2		c.1955A>C	p.Lys652Thr	missense	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.1955A>C	p.Lys652Thr	missense	Exon 12 of 27	ENSP00000343745.3
DICER1	ENST00000393063.6	TSL:1	c.1955A>C	p.Lys652Thr	missense	Exon 14 of 29	ENSP00000376783.1
DICER1	ENST00000527414.5	TSL:1	c.1955A>C	p.Lys652Thr	missense	Exon 12 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

251384

AF XY:

0.0000515

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000289

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:

0.00000753

AC:

AN:

1461410

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727040

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.000246

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111586

Other (OTH)

AF:

0.00

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

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:

0.0000131

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41446

American (AMR)

AF:

0.000131

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5202

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

DICER1-related disorder (1)

DICER1-related tumor predisposition (1)

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

Hereditary cancer-predisposing syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.53

MetaSVM

Benign

-0.79

MutationAssessor

Benign

0.48

PhyloP100

7.3

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.74

REVEL

Benign

0.26

Sift

Benign

0.28

Sift4G

Benign

0.57

Polyphen

1.0

Vest4

0.78

MutPred

0.56

Loss of methylation at K652 (P = 9e-04)

MVP

0.73

MPC

1.5

ClinPred

0.41

GERP RS

5.0

Varity_R

0.32

gMVP

0.64

Mutation Taster

=38/62

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over