14-95093521-A-G

Variant names:

• chr14-95093521-A-G
• rs2282265
• NM_177438.3:c.5364+367T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_177438.3(DICER1):​c.5364+367T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 152,320 control chromosomes in the GnomAD database, including 1,153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.11 (1153 hom., cov: 33)
• Consequence: DICER1 NM_177438.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0130
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• DICER1-related tumor predisposition

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• pleuropulmonary blastoma

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• DICER1 syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 14-95093521-A-G is Benign according to our data. Variant chr14-95093521-A-G is described in ClinVar as Benign. ClinVar VariationId is 1288348.Status of the report is criteria_provided_single_submitter, 1 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 rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.5364+367T>C		intron_variant	Intron 24 of 26	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.5364+367T>C		intron_variant	Intron 24 of 26	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16168 AN: 152202 Hom.: 1152 Cov.: 33

Gnomad AFR AF: 0.0805

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.150

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.113

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0888

Gnomad OTH AF: 0.105

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.106 AC: 16178 AN: 152320 Hom.: 1153 Cov.: 33 AF XY: 0.113 AC XY: 8396 AN XY: 74490

African (AFR) AF: 0.0805 AC: 3348 AN: 41580

American (AMR) AF: 0.150 AC: 2294 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 366 AN: 3472

East Asian (EAS) AF: 0.378 AC: 1954 AN: 5172

South Asian (SAS) AF: 0.147 AC: 709 AN: 4830

European-Finnish (FIN) AF: 0.113 AC: 1199 AN: 10618

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0888 AC: 6042 AN: 68026

Other (OTH) AF: 0.104 AC: 219 AN: 2114

Alfa AF: 0.0957 Hom.: 414

Bravo AF: 0.106

Asia WGS AF: 0.229 AC: 794 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 15, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.3
DANN	Benign	0.43
PhyloP100		0.013
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2282265; hg19: chr14-95559858;