rs147660793

Variant names:

• chr14-95133400-G-A
• rs147660793
• NM_177438.3:c.59C>T

Your query was ambiguous. Multiple possible variants found:

• chr14-95133400-G-A
• chr14-95133400-G-T

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.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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA332140/MONDO:0017288/024

• 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:12 O:1
• Conservation: PhyloP100: 9.47
• 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 -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.59C>T	p.Ala20Val	missense	Exon 2 of 27	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.59C>T	p.Ala20Val	missense	Exon 2 of 27	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.59C>T	p.Ala20Val	missense	Exon 2 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.59C>T	p.Ala20Val	missense	Exon 2 of 27	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.59C>T	p.Ala20Val	missense	Exon 4 of 29	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.59C>T	p.Ala20Val	missense	Exon 2 of 27	ENSP00000435681.1	Q9UPY3-1

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

GnomAD2 exomes AF: 0.000651 AC: 162 AN: 248888 AF XY: 0.000564

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 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

African (AFR) AF: 0.000299 AC: 10 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 68 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86242

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53400

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

European-Non Finnish (NFE) AF: 0.00129 AC: 1431 AN: 1111928

Other (OTH) AF: 0.00118 AC: 71 AN: 60384

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

African (AFR) AF: 0.000192 AC: 8 AN: 41566

American (AMR) AF: 0.000523 AC: 8 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10622

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

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00101 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

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	4	not provided (5)
-	-	3	DICER1-related tumor predisposition (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not specified (3)
-	-	1	DICER1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.033	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.55	N
PhyloP100		9.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.65
MVP		0.73
MPC		1.4
ClinPred		0.062	T
GERP RS		5.6
PromoterAI		0.0040	Neutral
Varity_R		0.26
gMVP		0.75
Mutation Taster		=56/44	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: rs147660793; hg19: chr14-95599737;