14-95107916-C-T

Variant names:

• chr14-95107916-C-T
• rs149242330
• NM_177438.3:c.2614G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BS1 BS2 BP4 BS3_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.2614G>A (p.Ala872Thr) variant in DICER1 has the highest population minor allele frequency in gnomAD v2.1.1 is 0.00119 in 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: 61756, 500031) and has been observed in a homozygous state in 5 healthy individuals (Internal lab contributors: 26957, 500031)(BS2). In vitro cleavage assay in HEK293 cells showed that this variant produces both 5p and 3p microRNAs from a pre-miRNA, indicating that this variant is unlikely to impact protein function (PMID:31342592)(BS3_Supporting). The computational predictor REVEL gives a score of 0.488, 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, BS3_Supporting, BP4. (Bayesian Points: -10; VCEP specifications version 1; 02/11/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA158264/MONDO:0017288/024

• Frequency:
  • Genomes: 𝑓 0.00074 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (3 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Benign reviewed by expert panel B:14 O:1
• Conservation: PhyloP100: 7.81
• Publications: 21 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 -10 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.
• BS3: 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.2614G>A	p.Ala872Thr	missense	Exon 16 of 27	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.2614G>A	p.Ala872Thr	missense	Exon 16 of 27	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.2614G>A	p.Ala872Thr	missense	Exon 16 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.2614G>A	p.Ala872Thr	missense	Exon 16 of 27	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.2614G>A	p.Ala872Thr	missense	Exon 18 of 29	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.2614G>A	p.Ala872Thr	missense	Exon 16 of 27	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.000736 AC: 112 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000829 AC: 208 AN: 251028 AF XY: 0.000840

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00123

Gnomad OTH exome AF: 0.00180

GnomAD4 exome AF: 0.000948 AC: 1385 AN: 1461736 Hom.: 3 Cov.: 34 AF XY: 0.000901 AC XY: 655 AN XY: 727188

African (AFR) AF: 0.000448 AC: 15 AN: 33478

American (AMR) AF: 0.00103 AC: 46 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.000545 AC: 47 AN: 86252

European-Finnish (FIN) AF: 0.000468 AC: 25 AN: 53408

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5768

European-Non Finnish (NFE) AF: 0.00107 AC: 1188 AN: 1111918

Other (OTH) AF: 0.000911 AC: 55 AN: 60386

GnomAD4 genome AF: 0.000736 AC: 112 AN: 152242 Hom.: 0 Cov.: 32 AF XY: 0.000712 AC XY: 53 AN XY: 74438

African (AFR) AF: 0.000578 AC: 24 AN: 41544

American (AMR) AF: 0.000719 AC: 11 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

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

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10590

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

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.000885 Hom.: 0

Bravo AF: 0.000706

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000840 AC: 102

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (6)
-	-	3	DICER1-related tumor predisposition (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	2	not provided (2)
-	-	1	DICER1-related disorder (1)
-	-	1	Pleuropulmonary blastoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Uncertain	0.59
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.052	T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.81	N
REVEL	Uncertain	0.49
Sift	Benign	0.44	T
Sift4G	Benign	0.75	T
Polyphen		1.0	D
Vest4		0.53
MVP		0.90
MPC		1.3
ClinPred		0.056	T
GERP RS		5.9
Varity_R		0.23
gMVP		0.76
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs149242330; hg19: chr14-95574253; COSMIC: COSV58617736; COSMIC: COSV58617736;