rs147660793

chr14-95133400-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_177438.3(DICER1):c.59C>T(p.Ala20Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,614,048 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A20T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (2 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:11 O:1
• Conservation: PhyloP100: 9.47

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, DICER1
• BP4: Computational evidence support a benign effect (MetaRNN=0.033258885).
• BP6: Variant 14-95133400-G-A is Benign according to our data. Variant chr14-95133400-G-A is described in ClinVar as [Benign]. Clinvar id is 133964.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000689 (105/152330) while in subpopulation NFE AF= 0.00109 (74/68026). AF 95% confidence interval is 0.000888. There are 0 homozygotes in gnomad4. There are 45 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 105 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.59C>T	p.Ala20Val	missense_variant	2/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.59C>T	p.Ala20Val	missense_variant	2/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes AF: 0.000690 AC: 105 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000651 AC: 162 AN: 248888 Hom.: 0 AF XY: 0.000564 AC XY: 76 AN XY: 134736

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00358

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000907

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00110 AC: 1614 AN: 1461718 Hom.: 2 Cov.: 31 AF XY: 0.00110 AC XY: 800 AN XY: 727150

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00260

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.00129

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.000689 AC: 105 AN: 152330 Hom.: 0 Cov.: 33 AF XY: 0.000604 AC XY: 45 AN XY: 74494

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.000593

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000535 AC: 65

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1 Benign:3

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	DICER1: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 06, 2021	This variant is associated with the following publications: (PMID: 28873162, 24728327) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 21, 2021	- -

DICER1-related tumor predisposition Benign:3

Benign, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	May 18, 2022	The NM_177438.2:c.59C>T is a missense variant in DICER1 predicted to cause substitution of Alanine by Valine at amino acid 20 (p.Ala20Val). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0009673 in the non-Finnish European population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). This variant has been observed in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (Internal lab contributors GTRs: 61756, 500031) and has been observed in a homozygous state in 3 healthy individuals (Internal lab contributors GTR: 500031)(BS2). The computational predictor REVEL gives a score of 0.302, which is below the threshold of 0.5, and the splice site predictors MaxEntScan and SpliceAI indicate that the variant has no impact on splicing, evidence that does not predict a damaging effect on DICER1 function (BP4). In summary, this variant meets the criteria to be classified as benign for DICER1 syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS1, BS2, BP4. (Bayesian Points: -9; VCEP specifications version 1; 02/11/2022). -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 13, 2021	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 28, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 27, 2021	- -

DICER1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 22, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.26	T;T;T;T;.;T;T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.033	T;T;T;T;T;T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.55	N;N;N;N;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.56	N;N;N;N;N;N;N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D;D;D;D;D;D;D
Sift4G	Uncertain	0.035	D;D;D;D;D;.;.
Polyphen		1.0	D;D;D;D;.;.;.
Vest4		0.65
MVP		0.73
MPC		1.4
ClinPred		0.062	T
GERP RS		5.6
Varity_R		0.26
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs147660793; hg19: chr14-95599737;