rs878855254

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_177438.3(DICER1):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000496 in 1,612,216 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★★).

Frequency

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

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

DICER1
NM_177438.3 start_lost

Scores

Clinical Significance

Uncertain significance reviewed by expert panel U:4

Conservation

PhyloP100: 5.30

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_pathogenic. Variant got 8 ACMG points.

PVS1

Start lost variant, no new inframe start found.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	2/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	2/27	1	NM_177438.3	P1	Q9UPY3-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00000408

AC:

AN:

245182

Hom.:

AF XY:

0.00

AC XY:

AN XY:

132624

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000916

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1459978

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726052

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00000540

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74382

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000312

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

DICER1-related tumor predisposition

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 14, 2024	This sequence change affects the initiator methionine of the DICER1 mRNA. The next in-frame methionine is located at codon 11. This variant is present in population databases (no rsID available, gnomAD 0.002%). Disruption of the initiator codon has been observed in individual(s) with hypothyroidism or renal cell carcinoma (PMID: 33630087). ClinVar contains an entry for this variant (Variation ID: 242076). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. -
Uncertain significance, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	May 18, 2022	The NM_177438.2:c.2T>C (p.Met1Thr) variant in DICER1 is predicted to disrupt the translation start site (p.M1?), but in-frame, downstream start sites are known to exist (PVS1 not met; PM4_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.00001755 (2/113946 alleles) in European non-Finnish population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets the criteria to be classified as a Variant of Uncertain Significance for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: PM4_Supporting. (Bayesian Points: 1; VCEP specifications version 1; 02/11/2022) -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Nov 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 06, 2023	The p.M1? variant (also known as c.2T>C) is located in coding exon 1 of the DICER1 gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). This alteration was identified in 5/92,296 unselected patients undergoing DICER1 testing via whole genome analysis (Mirshahi UL et al. JAMA Netw Open, 2021 02;4:e210112). Variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame; however, there is an in-frame methionine 10 amino acids from the initiation site, which may result in N-terminal truncation of unknown functional significance. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Uncertain

-0.040

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.24

T;T;T;T;.;T;T

Eigen

Benign

0.088

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.93

M_CAP

Benign

0.026

MetaRNN

Pathogenic

0.97

D;D;D;D;D;D;D

MetaSVM

Benign

-0.90

MutationTaster

Benign

0.98

N;N;N;N;N

PROVEAN

Benign

-0.34

N;N;N;N;N;N;N

REVEL

Benign

0.24

Sift

Uncertain

0.0030

D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D;.;.

Polyphen

0.0030

B;B;B;B;.;.;.

Vest4

0.79

MutPred

0.99

Gain of glycosylation at M1 (P = 0.0092);Gain of glycosylation at M1 (P = 0.0092);Gain of glycosylation at M1 (P = 0.0092);Gain of glycosylation at M1 (P = 0.0092);Gain of glycosylation at M1 (P = 0.0092);Gain of glycosylation at M1 (P = 0.0092);Gain of glycosylation at M1 (P = 0.0092);

MVP

0.91

ClinPred

0.96

GERP RS

5.6

Varity_R

0.48

gMVP

0.59

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