14-95099771-CAA-CAAAA

Position:

• chr14-95099771-CAA-CAAAA

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_177438.3(DICER1):​c.4206+7_4206+8dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 26,818 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.048 (29 hom., cov: 30)
  • Exomes 𝑓: 0.018 (101 hom.)
  • Failed GnomAD Quality Control
• Consequence: DICER1 NM_177438.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: -0.425

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 14-95099771-C-CAA is Benign according to our data. Variant chr14-95099771-C-CAA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221129.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=5}.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0589 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3	c.4206+7_4206+8dupTT		splice_region_variant, intron_variant		ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.4206+7_4206+8dupTT		splice_region_variant, intron_variant		1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes AF: 0.0482 AC: 1289 AN: 26738 Hom.: 29 Cov.: 30

Gnomad AFR AF: 0.0619

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0344

Gnomad ASJ AF: 0.0410

Gnomad EAS AF: 0.0155

Gnomad SAS AF: 0.0371

Gnomad FIN AF: 0.00540

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0394

Gnomad OTH AF: 0.0461

GnomAD3 exomes AF: 0.00964 AC: 1645 AN: 170614 Hom.: 568 AF XY: 0.00887 AC XY: 819 AN XY: 92356

Gnomad AFR exome AF: 0.0358

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.00212

Gnomad SAS exome AF: 0.0113

Gnomad FIN exome AF: 0.00414

Gnomad NFE exome AF: 0.00623

Gnomad OTH exome AF: 0.0115

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0183 AC: 4990 AN: 272402 Hom.: 101 Cov.: 34 AF XY: 0.0185 AC XY: 2470 AN XY: 133590

Gnomad4 AFR exome AF: 0.0546

Gnomad4 AMR exome AF: 0.0487

Gnomad4 ASJ exome AF: 0.0272

Gnomad4 EAS exome AF: 0.0183

Gnomad4 SAS exome AF: 0.0266

Gnomad4 FIN exome AF: 0.00322

Gnomad4 NFE exome AF: 0.0148

Gnomad4 OTH exome AF: 0.0253

GnomAD4 genome AF: 0.0484 AC: 1299 AN: 26818 Hom.: 29 Cov.: 30 AF XY: 0.0445 AC XY: 580 AN XY: 13022

Gnomad4 AFR AF: 0.0624

Gnomad4 AMR AF: 0.0344

Gnomad4 ASJ AF: 0.0410

Gnomad4 EAS AF: 0.0155

Gnomad4 SAS AF: 0.0367

Gnomad4 FIN AF: 0.00540

Gnomad4 NFE AF: 0.0394

Gnomad4 OTH AF: 0.0452

Alfa AF: 0.00806 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2017	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, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 17, 2019	- -
Uncertain significance, criteria provided, single submitter	curation	Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	Jul 01, 2019	ACMG criteria met: None -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Pleuropulmonary blastoma Benign:1

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555368535; hg19: chr14-95566108;