rs367764979

Positions:

• chr14-95099768-ACAC-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_177438.3(DICER1):​c.4206+9_4206+11del variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (15172 hom., cov: 0)
  • Exomes 𝑓: 0.42 (21516 hom.)
  • Failed GnomAD Quality Control
• Consequence: DICER1 NM_177438.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.410

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 -16 ACMG points.

• BP6: Variant 14-95099768-ACAC-A is Benign according to our data. Variant chr14-95099768-ACAC-A is described in ClinVar as [Likely_benign]. Clinvar id is 402592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-95099768-ACAC-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.4206+9_4206+11del		intron_variant		ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.4206+9_4206+11del		intron_variant		1	NM_177438.3	P1

Frequencies

GnomAD3 genomes AF: 0.475 AC: 64836 AN: 136574 Hom.: 15182 Cov.: 0

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.676

Gnomad AMR AF: 0.497

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.504

Gnomad SAS AF: 0.486

Gnomad FIN AF: 0.497

Gnomad MID AF: 0.514

Gnomad NFE AF: 0.571

Gnomad OTH AF: 0.463

GnomAD3 exomes AF: 0.155 AC: 32212 AN: 207618 Hom.: 11437 AF XY: 0.159 AC XY: 17875 AN XY: 112732

Gnomad AFR exome AF: 0.0974

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.0965

Gnomad SAS exome AF: 0.135

Gnomad FIN exome AF: 0.141

Gnomad NFE exome AF: 0.187

Gnomad OTH exome AF: 0.150

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR;InbreedingCoeff AF: 0.417 AC: 509306 AN: 1220414 Hom.: 21516 AF XY: 0.417 AC XY: 252860 AN XY: 606122

Gnomad4 AFR exome AF: 0.285

Gnomad4 AMR exome AF: 0.405

Gnomad4 ASJ exome AF: 0.413

Gnomad4 EAS exome AF: 0.403

Gnomad4 SAS exome AF: 0.410

Gnomad4 FIN exome AF: 0.413

Gnomad4 NFE exome AF: 0.423

Gnomad4 OTH exome AF: 0.412

GnomAD4 genome AF: 0.474 AC: 64839 AN: 136668 Hom.: 15172 Cov.: 0 AF XY: 0.473 AC XY: 31346 AN XY: 66296

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.497

Gnomad4 ASJ AF: 0.542

Gnomad4 EAS AF: 0.504

Gnomad4 SAS AF: 0.485

Gnomad4 FIN AF: 0.497

Gnomad4 NFE AF: 0.571

Gnomad4 OTH AF: 0.463

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 15, 2019

- -

DICER1-related tumor predisposition Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2016

This alteration is classified as likely benign based on a combination of the following: 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

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: rs367764979; hg19: chr14-95566105;