14-95093976-T-C

Variant names:

• chr14-95093976-T-C
• rs144259142
• NM_177438.3:c.5276A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. BS2 BP4 PM1_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_177438.2:c.5276A>G variant in DICER1 is a missense variant predicted to cause substitution of Lysine by Arginine at amino acid 1759 (p.Lys1759Arg). The highest population minor allele frequency in gnomAD v2.1.1 is 0.0001071 in European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). 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: 61756, 500031). The computational predictor REVEL gives a score of 0.444, 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). This variant resides within the RNase IIIb domain of DICER1, that is defined as a mutational hotspot and critical functional domain by the ClinGen DICER1 VCEP (PMID:31342592)(PM1_Supporting). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1 syndrome. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: (BS2, BP4, PM1_Supporting). (Bayesian Points: -4; VCEP specifications version 1; 02/11/2022). LINK:https://erepo.genome.network/evrepo/ui/classification/CA158282/MONDO:0017288/024

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:6 O:1
• Conservation: PhyloP100: 7.61
• Publications: 6 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

Specifications for DICER1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• BP4: 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.5276A>G	p.Lys1759Arg	missense	Exon 24 of 27	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.5276A>G	p.Lys1759Arg	missense	Exon 24 of 27	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.5276A>G	p.Lys1759Arg	missense	Exon 24 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.5276A>G	p.Lys1759Arg	missense	Exon 24 of 27	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.5276A>G	p.Lys1759Arg	missense	Exon 26 of 29	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.5276A>G	p.Lys1759Arg	missense	Exon 24 of 27	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.0000657 AC: 10 AN: 152144 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

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: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000557 AC: 14 AN: 251452 AF XY: 0.0000515

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000554 AC: 81 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.0000550 AC XY: 40 AN XY: 727234

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5768

European-Non Finnish (NFE) AF: 0.0000540 AC: 60 AN: 1111978

Other (OTH) AF: 0.000215 AC: 13 AN: 60396

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152144 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74300

African (AFR) AF: 0.0000241 AC: 1 AN: 41438

American (AMR) AF: 0.000196 AC: 3 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
Eigen	Benign	0.032
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-0.060	N
PhyloP100		7.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.53	N
REVEL	Uncertain	0.44
Sift	Benign	0.55	T
Sift4G	Benign	1.0	T
Polyphen		1.0	D
Vest4		0.68
MVP		0.89
MPC		2.2
ClinPred		0.11	T
GERP RS		5.3
Varity_R		0.50
gMVP		0.39
Mutation Taster		=69/31	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: rs144259142; hg19: chr14-95560313;