rs544960260

chr14-95096657-ATCC-Achr14-95096657-ATCC-ATCCTCC

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_177438.3(DICER1):c.4260_4262del(p.Glu1420del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00174 in 1,612,370 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E1420E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (3 hom.)
• Consequence: DICER1 NM_177438.3 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:8 O:1
• Conservation: PhyloP100: 4.95

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 -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_177438.3
• BP6: Variant 14-95096657-ATCC-A is Benign according to our data. Variant chr14-95096657-ATCC-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 133971.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=3, Uncertain_significance=2, not_provided=1}. Variant chr14-95096657-ATCC-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00121 (184/152044) while in subpopulation NFE AF= 0.0024 (163/67950). AF 95% confidence interval is 0.0021. There are 1 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 184 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.4260_4262del	p.Glu1420del	inframe_deletion	23/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.4260_4262del	p.Glu1420del	inframe_deletion	23/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes AF: 0.00121 AC: 184 AN: 151926 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.000378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00240

Gnomad OTH AF: 0.000960

GnomAD3 exomes AF: 0.00121 AC: 299 AN: 246384 Hom.: 1 AF XY: 0.00134 AC XY: 179 AN XY: 133396

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.000100

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000928

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00229

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.00179 AC: 2615 AN: 1460326 Hom.: 3 AF XY: 0.00177 AC XY: 1283 AN XY: 726468

Gnomad4 AFR exome AF: 0.000240

Gnomad4 AMR exome AF: 0.000247

Gnomad4 ASJ exome AF: 0.000307

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000721

Gnomad4 FIN exome AF: 0.000469

Gnomad4 NFE exome AF: 0.00216

Gnomad4 OTH exome AF: 0.00169

GnomAD4 genome AF: 0.00121 AC: 184 AN: 152044 Hom.: 1 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74348

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000624

Gnomad4 FIN AF: 0.000378

Gnomad4 NFE AF: 0.00240

Gnomad4 OTH AF: 0.000950

Alfa AF: 0.00149 Hom.: 1

Bravo AF: 0.000997

EpiCase AF: 0.00142

EpiControl AF: 0.00214

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:2 Benign:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	curation	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jul 01, 2019	ACMG criteria met: PM4, BS1 -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 29, 2021	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	DICER1: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 21, 2021	This variant is associated with the following publications: (PMID: 21266384, 24728327, 22180160, 29187512, 29474644) -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 17, 2019	This alteration is classified as likely 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 06, 2020	- -

Pleuropulmonary blastoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

DICER1-related tumor predisposition Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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: rs544960260; hg19: chr14-95562994;