rs1057035

Variant names:

• chr14-95087805-T-C
• rs1057035
• NM_177438.3:c.*2693A>G

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.*2693A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 233,052 control chromosomes in the GnomAD database, including 10,371 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (6358 hom., cov: 32)
  • Exomes 𝑓: 0.30 (4013 hom.)
• Consequence: DICER1 NM_177438.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.256
• Publications: 73 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=-0.88).
• BP6: Variant 14-95087805-T-C is Benign according to our data. Variant chr14-95087805-T-C is described in ClinVar as Benign. ClinVar VariationId is 315063.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.*2693A>G		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.*2693A>G		3_prime_UTR_variant	Exon 27 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes AF: 0.258 AC: 39172 AN: 152014 Hom.: 6360 Cov.: 32

Gnomad AFR AF: 0.0800

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.136

Gnomad SAS AF: 0.0859

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.273

GnomAD4 exome AF: 0.298 AC: 24079 AN: 80920 Hom.: 4013 Cov.: 0 AF XY: 0.297 AC XY: 11063 AN XY: 37190

African (AFR) AF: 0.0814 AC: 317 AN: 3892

American (AMR) AF: 0.336 AC: 839 AN: 2500

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1684 AN: 5118

East Asian (EAS) AF: 0.112 AC: 1273 AN: 11398

South Asian (SAS) AF: 0.107 AC: 75 AN: 700

European-Finnish (FIN) AF: 0.288 AC: 19 AN: 66

Middle Eastern (MID) AF: 0.205 AC: 101 AN: 492

European-Non Finnish (NFE) AF: 0.355 AC: 17731 AN: 49990

Other (OTH) AF: 0.302 AC: 2040 AN: 6764

GnomAD4 genome AF: 0.257 AC: 39171 AN: 152132 Hom.: 6358 Cov.: 32 AF XY: 0.251 AC XY: 18665 AN XY: 74376

African (AFR) AF: 0.0799 AC: 3317 AN: 41530

American (AMR) AF: 0.318 AC: 4855 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 1070 AN: 3466

East Asian (EAS) AF: 0.135 AC: 700 AN: 5172

South Asian (SAS) AF: 0.0857 AC: 414 AN: 4828

European-Finnish (FIN) AF: 0.295 AC: 3113 AN: 10564

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24624 AN: 67974

Other (OTH) AF: 0.270 AC: 570 AN: 2110

Alfa AF: 0.309 Hom.: 17218

Bravo AF: 0.256

Asia WGS AF: 0.126 AC: 440 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DICER1-related tumor predisposition Benign:2

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.92
DANN	Benign	0.55
PhyloP100		0.26
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1057035; hg19: chr14-95554142;