rs3742330

Variant names:

• chr14-95087025-A-G
• rs3742330
• NM_177438.3:c.*3473T>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 92 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 -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 VariationId 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 rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.*3473T>C		3_prime_UTR_variant	Exon 27 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.*3473T>C		3_prime_UTR_variant	Exon 27 of 27	1	NM_177438.3	ENSP00000343745.3

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

African (AFR) AF: 0.0224 AC: 87 AN: 3876

American (AMR) AF: 0.128 AC: 319 AN: 2484

Ashkenazi Jewish (ASJ) AF: 0.0975 AC: 498 AN: 5106

East Asian (EAS) AF: 0.453 AC: 5126 AN: 11324

South Asian (SAS) AF: 0.172 AC: 120 AN: 696

European-Finnish (FIN) AF: 0.0980 AC: 20 AN: 204

Middle Eastern (MID) AF: 0.120 AC: 59 AN: 492

European-Non Finnish (NFE) AF: 0.0885 AC: 4407 AN: 49816

Other (OTH) AF: 0.0999 AC: 673 AN: 6738

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

African (AFR) AF: 0.0281 AC: 1170 AN: 41580

American (AMR) AF: 0.144 AC: 2208 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 370 AN: 3470

East Asian (EAS) AF: 0.377 AC: 1953 AN: 5174

South Asian (SAS) AF: 0.147 AC: 706 AN: 4816

European-Finnish (FIN) AF: 0.114 AC: 1209 AN: 10596

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0909 AC: 6186 AN: 68020

Other (OTH) AF: 0.0909 AC: 192 AN: 2112

Alfa AF: 0.0944 Hom.: 1538

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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

DICER1-related tumor predisposition Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.38
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: rs3742330; hg19: chr14-95553362;