rs8019857

Positions:

• chr14-95105738-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000343455.8(DICER1):​c.3033G>A​(p.Ala1011=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00627 in 1,614,094 control chromosomes in the GnomAD database, including 594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1011A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.033 (312 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (282 hom.)
• Consequence: DICER1 ENST00000343455.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.86

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 14-95105738-C-T is Benign according to our data. Variant chr14-95105738-C-T is described in ClinVar as [Benign]. Clinvar id is 261921.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95105738-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.114 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3	c.3033G>A	p.Ala1011=	synonymous_variant	19/27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.3033G>A	p.Ala1011=	synonymous_variant	19/27	1	NM_177438.3	ENSP00000343745	P1

Frequencies

GnomAD3 genomes AF: 0.0333 AC: 5065 AN: 152170 Hom.: 311 Cov.: 33

Gnomad AFR AF: 0.117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.0177

GnomAD3 exomes AF: 0.00890 AC: 2238 AN: 251342 Hom.: 125 AF XY: 0.00643 AC XY: 873 AN XY: 135850

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.00546

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000719

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.00345 AC: 5045 AN: 1461806 Hom.: 282 Cov.: 31 AF XY: 0.00294 AC XY: 2136 AN XY: 727216

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.00610

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000742

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.00811

GnomAD4 genome AF: 0.0333 AC: 5077 AN: 152288 Hom.: 312 Cov.: 33 AF XY: 0.0323 AC XY: 2405 AN XY: 74484

Gnomad4 AFR AF: 0.117

Gnomad4 AMR AF: 0.0114

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.0175

Alfa AF: 0.00812 Hom.: 98

Bravo AF: 0.0380

Asia WGS AF: 0.00837 AC: 30 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000237

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 13, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

DICER1-related tumor predisposition Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Pleuropulmonary blastoma Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 25, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	3.4
DANN	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs8019857; hg19: chr14-95572075;