rs996633792

Positions:

chr14-95096637-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BS2_SupportingBP4

This summary comes from the ClinGen Evidence Repository: NM_177438.3(DICER1):c.4283T>A variant in DICER1 is a missense variant predicted to cause substitution of methionine by lysine at amino acid 1428 (p.Met1802Lys). This variant received a total of 0.5 phenotype points in a single proband (PS4 not met; Internal lab contributors SCV001509541.1). This variant has also been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors SCV001509541.1, SCV001444307.1). The highest population minor allele frequency in gnomAD v2.1.1 non-cancer is 0.00008606 (3/34860 alleles) in Latino/Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.115; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.2.0; 01/09/2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA16614307/MONDO:0100216/024

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

DICER1
NM_177438.3 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:4B:1

Conservation

PhyloP100: 0.102

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

BS2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3 linkuse as main transcript	c.4283T>A	p.Met1428Lys	missense_variant	23/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8 linkuse as main transcript	c.4283T>A	p.Met1428Lys	missense_variant	23/27	1	NM_177438.3	P1	Q9UPY3-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000121

AC:

AN:

247190

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

133806

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000874

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.0000137

AC:

AN:

1459992

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726258

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000898

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 02, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 14, 2022	The p.M1428K variant (also known as c.4283T>A), located in coding exon 22 of the DICER1 gene, results from a T to A substitution at nucleotide position 4283. The methionine at codon 1428 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

DICER1-related tumor predisposition

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1428 of the DICER1 protein (p.Met1428Lys). This variant is present in population databases (no rsID available, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with DICER1-related conditions. ClinVar contains an entry for this variant (Variation ID: 412118). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely benign, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	Jan 09, 2024	NM_177438.3(DICER1):c.4283T>A variant in DICER1 is a missense variant predicted to cause substitution of methionine by lysine at amino acid 1428 (p.Met1802Lys). This variant received a total of 0.5 phenotype points in a single proband (PS4 not met; Internal lab contributors SCV001509541.1). This variant has also been seen in 10 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2_Supporting; Internal lab contributors SCV001509541.1, SCV001444307.1). The highest population minor allele frequency in gnomAD v2.1.1 non-cancer is 0.00008606 (3/34860 alleles) in Latino/Admixed American population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.115; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2_Supporting, BP4. (Bayesian Points: -2; VCEP specifications version 1.2.0; 01/09/2024) -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 10, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.85

DEOGEN2

Benign

0.24

T;T;T;T;.;.

Eigen

Benign

-0.70

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.83

.;.;T;.;T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.13

T;T;T;T;T;T

MetaSVM

Benign

-0.69

MutationAssessor

Benign

1.5

L;L;L;L;.;L

MutationTaster

Benign

0.94

N;N;N;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.39

N;N;N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.034

D;D;D;D;D;D

Sift4G

Benign

0.23

T;T;T;T;T;D

Polyphen

0.0030

B;B;B;B;.;.

Vest4

0.49

MutPred

0.46

Gain of ubiquitination at M1428 (P = 0.0054);Gain of ubiquitination at M1428 (P = 0.0054);Gain of ubiquitination at M1428 (P = 0.0054);Gain of ubiquitination at M1428 (P = 0.0054);.;Gain of ubiquitination at M1428 (P = 0.0054);

MVP

0.75

MPC

0.81

ClinPred

0.027

GERP RS

-1.4

Varity_R

0.27

gMVP

0.55

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over