rs766236360

chr14-95099756-ACACACACACACACAC-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_177438.3(DICER1):c.4206+9_4206+23del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000924 in 1,558,664 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: DICER1 NM_177438.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.829

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 -16 ACMG points.

• BP6: Variant 14-95099756-ACACACACACACACAC-A is Benign according to our data. Variant chr14-95099756-ACACACACACACACAC-A is described in ClinVar as [Likely_benign]. Clinvar id is 543700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.0000965 (136/1408658) while in subpopulation AMR AF= 0.00056 (24/42820). AF 95% confidence interval is 0.000386. There are 0 homozygotes in gnomad4_exome. There are 69 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.4206+9_4206+23del		intron_variant		ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.4206+9_4206+23del		intron_variant		1	NM_177438.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000534 AC: 8 AN: 149894 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000261 AC: 60 AN: 230324 Hom.: 2 AF XY: 0.000255 AC XY: 32 AN XY: 125562

Gnomad AFR exome AF: 0.000363

Gnomad AMR exome AF: 0.000460

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000516

Gnomad SAS exome AF: 0.000310

Gnomad FIN exome AF: 0.000208

Gnomad NFE exome AF: 0.000140

Gnomad OTH exome AF: 0.000693

GnomAD4 exome AF: 0.0000965 AC: 136 AN: 1408658 Hom.: 0 AF XY: 0.0000984 AC XY: 69 AN XY: 700932

Gnomad4 AFR exome AF: 0.000157

Gnomad4 AMR exome AF: 0.000560

Gnomad4 ASJ exome AF: 0.0000396

Gnomad4 EAS exome AF: 0.000427

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.000165

Gnomad4 NFE exome AF: 0.0000500

Gnomad4 OTH exome AF: 0.0000688

GnomAD4 genome AF: 0.0000533 AC: 8 AN: 150006 Hom.: 0 Cov.: 24 AF XY: 0.0000682 AC XY: 5 AN XY: 73338

Gnomad4 AFR AF: 0.0000252

Gnomad4 AMR AF: 0.0000659

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Feb 06, 2024

- -

DICER1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 13, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

DICER1-related tumor predisposition Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 30, 2020

- -

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: rs766236360; hg19: chr14-95566093;