rs140875148

Positions:

• chr14-95096010-G-A
• chr14-95096010-G-C
• chr14-95096010-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BS2 BP4 BS1

This summary comes from the ClinGen Evidence Repository: NM_177438.2(DICER1):c.4910C>T variant in DICER1 is a missense variant predicted to cause substitution of serine by leucine at amino acid 1637 (p.Ser1637Leu). The highest population minor allele frequency in gnomAD v2.1.1 non-cancer is 0.0026 (61/23614 alleles) in African/African-American population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors/GTRs: 61756, 500031). The computational predictor REVEL gives a score of 0.065, 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA7330772/MONDO:0017288/024

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 3.24

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 -9 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DICER1	NM_177438.3	c.4910C>T	p.Ser1637Leu	missense_variant	23/27	ENST00000343455.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DICER1	ENST00000343455.8	c.4910C>T	p.Ser1637Leu	missense_variant	23/27	1	NM_177438.3	P1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000251 AC: 63 AN: 251414 Hom.: 0 AF XY: 0.000191 AC XY: 26 AN XY: 135874

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000107 AC: 156 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.0000866 AC XY: 63 AN XY: 727244

Gnomad4 AFR exome AF: 0.00275

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74474

Gnomad4 AFR AF: 0.00303

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.000185 Hom.: 0

Bravo AF: 0.00136

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000272 AC: 33

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

DICER1-related tumor predisposition Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, reviewed by expert panel	curation	ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen	May 18, 2022	NM_177438.2(DICER1):c.4910C>T variant in DICER1 is a missense variant predicted to cause substitution of serine by leucine at amino acid 1637 (p.Ser1637Leu). The highest population minor allele frequency in gnomAD v2.1.1 non-cancer is 0.0026 (61/23614 alleles) in African/African-American population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; Internal lab contributors/GTRs: 61756, 500031). The computational predictor REVEL gives a score of 0.065, 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	Jan 25, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 31, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 01, 2024	This alteration is classified as 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. -

DICER1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2019

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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

May 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Benign	0.38
DEOGEN2	Benign	0.17	T;T;T;T;.;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.16	N
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.0042	T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-1.3	N;N;N;N;.;N
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.22	N;N;N;N;N;N
REVEL	Benign	0.065
Sift	Benign	0.69	T;T;T;T;T;T
Sift4G	Benign	0.32	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;.;.
Vest4		0.16
MVP		0.59
MPC		0.43
ClinPred		0.0010	T
GERP RS		3.6
Varity_R		0.028
gMVP		0.26

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: rs140875148; hg19: chr14-95562347;