rs1057035

Positions:

• chr14-95087805-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_177438.3(DICER1):​c.*2693A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 233,052 control chromosomes in the GnomAD database, including 10,371 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6358 hom., cov: 32)
  • Exomes 𝑓: 0.30 (4013 hom.)
• Consequence: DICER1 NM_177438.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.256

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-95087805-T-C is Benign according to our data. Variant chr14-95087805-T-C is described in ClinVar as [Benign]. Clinvar id is 315063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.*2693A>G		3_prime_UTR_variant	27/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.*2693A>G		3_prime_UTR_variant	27/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39172 AN: 152014 Hom.: 6360 Cov.: 32

Gnomad AFR AF: 0.0800

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.0859

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.273

GnomAD4 exome AF: 0.298 AC: 24079 AN: 80920 Hom.: 4013 Cov.: 0 AF XY: 0.297 AC XY: 11063 AN XY: 37190

Gnomad4 AFR exome AF: 0.0814

Gnomad4 AMR exome AF: 0.336

Gnomad4 ASJ exome AF: 0.329

Gnomad4 EAS exome AF: 0.112

Gnomad4 SAS exome AF: 0.107

Gnomad4 FIN exome AF: 0.288

Gnomad4 NFE exome AF: 0.355

Gnomad4 OTH exome AF: 0.302

GnomAD4 genome AF: 0.257 AC: 39171 AN: 152132 Hom.: 6358 Cov.: 32 AF XY: 0.251 AC XY: 18665 AN XY: 74376

Gnomad4 AFR AF: 0.0799

Gnomad4 AMR AF: 0.318

Gnomad4 ASJ AF: 0.309

Gnomad4 EAS AF: 0.135

Gnomad4 SAS AF: 0.0857

Gnomad4 FIN AF: 0.295

Gnomad4 NFE AF: 0.362

Gnomad4 OTH AF: 0.270

Alfa AF: 0.331 Hom.: 12225

Bravo AF: 0.256

Asia WGS AF: 0.126 AC: 440 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DICER1-related tumor predisposition Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 04, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.92
DANN	Benign	0.55
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1057035; hg19: chr14-95554142;