14-95086612-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_177438.3(DICER1):c.*3886C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00388 in 233,206 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0041 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0034 (1 hom.)
• Consequence: DICER1 NM_177438.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.294

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 14-95086612-G-A is Benign according to our data. Variant chr14-95086612-G-A is described in ClinVar as [Benign]. Clinvar id is 315047.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00415 (631/152220) while in subpopulation SAS AF= 0.0141 (68/4826). AF 95% confidence interval is 0.0114. There are 5 homozygotes in gnomad4. There are 373 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 630 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.*3886C>T		3_prime_UTR_variant	27/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.*3886C>T		3_prime_UTR_variant	27/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes AF: 0.00414 AC: 630 AN: 152102 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0181

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00381

Gnomad OTH AF: 0.00287

GnomAD4 exome AF: 0.00340 AC: 275 AN: 80986 Hom.: 1 Cov.: 0 AF XY: 0.00367 AC XY: 137 AN XY: 37304

Gnomad4 AFR exome AF: 0.000516

Gnomad4 AMR exome AF: 0.00160

Gnomad4 ASJ exome AF: 0.00392

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0230

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.00405

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.00415 AC: 631 AN: 152220 Hom.: 5 Cov.: 33 AF XY: 0.00501 AC XY: 373 AN XY: 74420

Gnomad4 AFR AF: 0.000842

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0141

Gnomad4 FIN AF: 0.0181

Gnomad4 NFE AF: 0.00381

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00325 Hom.: 1

Bravo AF: 0.00283

Asia WGS AF: 0.00550 AC: 19 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.80
Cadd	Benign	0.43
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11556997; hg19: chr14-95552949;