14-95112338-T-C

Variant names:

• chr14-95112338-T-C
• rs2297730
• NM_177438.3:c.2041-91A>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.2041-91A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.128 in 1,053,282 control chromosomes in the GnomAD database, including 13,130 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3612 hom., cov: 32)
  • Exomes 𝑓: 0.12 (9518 hom.)
• Consequence: DICER1 NM_177438.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0620
• Publications: 7 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=-0.8).
• BP6: Variant 14-95112338-T-C is Benign according to our data. Variant chr14-95112338-T-C is described in ClinVar as Benign. ClinVar VariationId is 676900.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.366 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.2041-91A>G		intron_variant	Intron 12 of 26	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.2041-91A>G		intron_variant	Intron 12 of 26	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27712 AN: 151904 Hom.: 3605 Cov.: 32

Gnomad AFR AF: 0.346

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.180

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0895

Gnomad OTH AF: 0.154

GnomAD4 exome AF: 0.118 AC: 106705 AN: 901260 Hom.: 9518 AF XY: 0.119 AC XY: 55317 AN XY: 464654

African (AFR) AF: 0.344 AC: 7529 AN: 21862

American (AMR) AF: 0.176 AC: 6060 AN: 34384

Ashkenazi Jewish (ASJ) AF: 0.0981 AC: 2129 AN: 21710

East Asian (EAS) AF: 0.428 AC: 15495 AN: 36180

South Asian (SAS) AF: 0.151 AC: 10144 AN: 67218

European-Finnish (FIN) AF: 0.108 AC: 5520 AN: 51168

Middle Eastern (MID) AF: 0.119 AC: 557 AN: 4670

European-Non Finnish (NFE) AF: 0.0865 AC: 53872 AN: 622608

Other (OTH) AF: 0.130 AC: 5399 AN: 41460

GnomAD4 genome AF: 0.183 AC: 27755 AN: 152022 Hom.: 3612 Cov.: 32 AF XY: 0.186 AC XY: 13791 AN XY: 74302

African (AFR) AF: 0.346 AC: 14329 AN: 41438

American (AMR) AF: 0.180 AC: 2753 AN: 15278

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

East Asian (EAS) AF: 0.380 AC: 1959 AN: 5154

South Asian (SAS) AF: 0.146 AC: 703 AN: 4822

European-Finnish (FIN) AF: 0.112 AC: 1187 AN: 10570

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0895 AC: 6083 AN: 67974

Other (OTH) AF: 0.153 AC: 323 AN: 2110

Alfa AF: 0.149 Hom.: 431

Bravo AF: 0.193

Asia WGS AF: 0.253 AC: 878 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 16, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

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	-0.80
CADD	Benign	7.8
DANN	Benign	0.82
PhyloP100		-0.062
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: rs2297730; hg19: chr14-95578675; COSMIC: COSV58616604; COSMIC: COSV58616604;