rs139536688

Variant names:

• chr14-95099787-T-C
• rs139536688
• NM_177438.3:c.4199A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS2 BP4

This summary comes from the ClinGen Evidence Repository: The NM_177438.3:c.4199A>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 1400 (p.Asp1400Gly). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory and has been observed in a homozygous state in one healthy individual (BS2; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.000047 (76/1612760 alleles) with a highest population minor allele frequency of 0.000056 (66/1179824 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.142; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2, BP4. (Bayesian Points: -5; VCEP specifications version 1.3.0; 06/24/2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA7330935/MONDO:0100216/024

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:4
• Conservation: PhyloP100: 4.54
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DICER1	NM_177438.3	c.4199A>G	p.Asp1400Gly	missense_variant	Exon 22 of 27	ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.4199A>G	p.Asp1400Gly	missense_variant	Exon 22 of 27	1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151580 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000280 AC: 7 AN: 250284 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000500 AC: 73 AN: 1461180 Hom.: 0 Cov.: 34 AF XY: 0.0000523 AC XY: 38 AN XY: 726920

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39672

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111896

Other (OTH) AF: 0.0000331 AC: 2 AN: 60366

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151580 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74072

African (AFR) AF: 0.00 AC: 0 AN: 41094

American (AMR) AF: 0.00 AC: 0 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000849 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4 Benign:4

Revision: reviewed by expert panel

Submissions by phenotype

DICER1-related tumor predisposition Benign:3

Jun 24, 2025

ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel, ClinGen

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The NM_177438.3:c.4199A>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 1400 (p.Asp1400Gly). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory and has been observed in a homozygous state in one healthy individual (BS2; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.000047 (76/1612760 alleles) with a highest population minor allele frequency of 0.000056 (66/1179824 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.142; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2, BP4. (Bayesian Points: -5; VCEP specifications version 1.3.0; 06/24/2025) -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Hereditary cancer-predisposing syndrome Uncertain:2

Aug 09, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D1400G variant (also known as c.4199A>G), located in coding exon 21 of the DICER1 gene, results from an A to G substitution at nucleotide position 4199. The aspartic acid at codon 1400 is replaced by glycine, an amino acid with similar properties. This variant has been reported in a two-year-old female with pleuropulmonary blastoma and a family history of pleuropulmonary blastoma and pineoblastoma. This patient was also reported to have a DICER1 c.2437-2A>G variant, which was called likely pathogenic by the authors; however, the phase of the variants (whether in cis or trans) was not reported (Leckey BD et al. BMJ Case Rep. 2019 Jan;12). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Oct 25, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

DICER1-related disorder Uncertain:1

May 04, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The DICER1 c.4199A>G variant is predicted to result in the amino acid substitution p.Asp1400Gly. This variant has been reported in the germline of two siblings with pleuropulmonary blastoma that also harbored a germline loss of function variant in DICER1 (Leckey et al. 2019. PubMed ID: 30665929). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-95566124-T-C) and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/412173/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DICER1 p.Asp1400Gly variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs139536688), ClinVar (classified as a VUS by Invitae) and LOVD 3.0. The variant was also identified in control databases in 7 of 250284 chromosomes at a frequency of 0.000028 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 1 of 10076 chromosomes (freq: 0.000099), European (non-Finnish) in 5 of 113570 chromosomes (freq: 0.000044) and South Asian in 1 of 30606 chromosomes (freq: 0.000033), while the variant was not observed in the African, Latino, East Asian, European (Finnish), and Other populations. The p.Asp1400 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan) predict a greater than 10% difference in splicing and the creation of a new 5' splice site; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Benign:1

Jul 01, 2019

Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

ACMG criteria met: BP1, BP2, BP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T;T;T;.;.
Eigen	Benign	0.068
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;.;D;.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.18	T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.2	L;L;L;L;.;L
PhyloP100		4.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.54	N;N;N;N;N;N
REVEL	Benign	0.14
Sift	Benign	0.12	T;T;T;T;D;T
Sift4G	Benign	0.45	T;T;T;T;T;T
Polyphen		0.017	B;B;B;B;.;.
Vest4		0.28
MVP		0.83
MPC		0.78
ClinPred		0.13	T
GERP RS		5.8
Varity_R		0.22
gMVP		0.39
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs139536688; hg19: chr14-95566124;