rs139786661

Variant names:

• chr14-95103968-A-G
• rs139786661
• NM_177438.3:c.3428T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BS1 BS2 BP4

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.3428T>C variant in DICER1 is a missense variant predicted to cause substitution of leucine by proline at amino acid 1143 (p.Leu1143Pro). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory (BS2; GTRs: 500031, 61756). The highest population minor allele frequency in gnomAD v2.1.1 (non-cancer) is 0.0029 (69/23442 alleles; FAF=0.0020) in African/African-American population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). The computational predictor REVEL gives a score of 0.102, 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: BS2, BS1, BP4. (Bayesian Points: -9; VCEP specifications version 1; 02/11/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA349475/MONDO:0017288/024

• Frequency:
  • Genomes: 𝑓 0.00069 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000083 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Benign reviewed by expert panel B:11
• Conservation: PhyloP100: 1.75
• Publications: 2 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 -9 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177438.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	NM_177438.3	MANE Select	c.3428T>C	p.Leu1143Pro	missense	Exon 21 of 27	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.3428T>C	p.Leu1143Pro	missense	Exon 21 of 27	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.3428T>C	p.Leu1143Pro	missense	Exon 21 of 27	NP_001278557.1	Q9UPY3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.3428T>C	p.Leu1143Pro	missense	Exon 21 of 27	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.3428T>C	p.Leu1143Pro	missense	Exon 23 of 29	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.3428T>C	p.Leu1143Pro	missense	Exon 21 of 27	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152208 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000171 AC: 43 AN: 250930 AF XY: 0.0000958

Gnomad AFR exome AF: 0.00261

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000828 AC: 121 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000743 AC XY: 54 AN XY: 727238

African (AFR) AF: 0.00296 AC: 99 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112006

Other (OTH) AF: 0.000248 AC: 15 AN: 60392

GnomAD4 genome AF: 0.000689 AC: 105 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.000685 AC XY: 51 AN XY: 74476

African (AFR) AF: 0.00245 AC: 102 AN: 41574

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.000748

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000214 AC: 26

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	DICER1-related tumor predisposition (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	DICER1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.89
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.7
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.31	N
REVEL	Benign	0.10
Sift	Benign	0.24	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.23
MVP		0.70
MPC		0.79
ClinPred		0.018	T
GERP RS		-1.4
Varity_R		0.076
gMVP		0.61
Mutation Taster		=82/18	polymorphism

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: rs139786661; hg19: chr14-95570305;