rs3742330

Positions:

• chr14-95087025-A-G

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.*3473T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 233,008 control chromosomes in the GnomAD database, including 2,490 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (1023 hom., cov: 33)
  • Exomes 𝑓: 0.14 (1467 hom.)
• Consequence: DICER1 NM_177438.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.377

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=-0.83).
• BP6: Variant 14-95087025-A-G is Benign according to our data. Variant chr14-95087025-A-G is described in ClinVar as [Benign]. Clinvar id is 315050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3	c.*3473T>C		3_prime_UTR_variant	27/27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.*3473T>C		3_prime_UTR_variant	27/27	1	NM_177438.3	ENSP00000343745	P1

Frequencies

GnomAD3 genomes AF: 0.0923 AC: 14040 AN: 152154 Hom.: 1021 Cov.: 33

Gnomad AFR AF: 0.0282

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.376

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0909

Gnomad OTH AF: 0.0919

GnomAD4 exome AF: 0.140 AC: 11309 AN: 80736 Hom.: 1467 Cov.: 0 AF XY: 0.139 AC XY: 5155 AN XY: 37132

Gnomad4 AFR exome AF: 0.0224

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.0975

Gnomad4 EAS exome AF: 0.453

Gnomad4 SAS exome AF: 0.172

Gnomad4 FIN exome AF: 0.0980

Gnomad4 NFE exome AF: 0.0885

Gnomad4 OTH exome AF: 0.0999

GnomAD4 genome AF: 0.0922 AC: 14039 AN: 152272 Hom.: 1023 Cov.: 33 AF XY: 0.0988 AC XY: 7355 AN XY: 74452

Gnomad4 AFR AF: 0.0281

Gnomad4 AMR AF: 0.144

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.377

Gnomad4 SAS AF: 0.147

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.0909

Gnomad4 OTH AF: 0.0909

Alfa AF: 0.0940 Hom.: 1015

Bravo AF: 0.0900

Asia WGS AF: 0.225 AC: 782 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

DICER1-related tumor predisposition Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.46

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: rs3742330; hg19: chr14-95553362;