chr14-95096010-G-A

Variant names:

• chr14-95096010-G-A
• rs140875148
• NM_177438.3:c.4910C>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: NM_177438.2(DICER1):c.4910C>T variant in DICER1 is a missense variant predicted to cause substitution of serine by leucine at amino acid 1637 (p.Ser1637Leu). The highest population minor allele frequency in gnomAD v2.1.1 non-cancer is 0.0026 (61/23614 alleles) in African/African-American population, which is higher than the ClinGen DICER1 VCEP threshold (>0.0003) for BS1, and therefore meets this criterion (BS1). 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/GTRs: 61756, 500031). The computational predictor REVEL gives a score of 0.065, 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/CA7330772/MONDO:0017288/024

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: DICER1 NM_030621.4 missense
• Clinical Significance: Benign reviewed by expert panel B:7
• Conservation: PhyloP100: 3.24
• 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_030621.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	NM_177438.3	MANE Select	c.4910C>T	p.Ser1637Leu	missense	Exon 23 of 27	NP_803187.1
	DICER1	NM_001271282.3		c.4910C>T	p.Ser1637Leu	missense	Exon 23 of 27	NP_001258211.1
	DICER1	NM_001291628.2		c.4910C>T	p.Ser1637Leu	missense	Exon 23 of 27	NP_001278557.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.4910C>T	p.Ser1637Leu	missense	Exon 23 of 27	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.4910C>T	p.Ser1637Leu	missense	Exon 25 of 29	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.4910C>T	p.Ser1637Leu	missense	Exon 23 of 27	ENSP00000435681.1

Frequencies

GnomAD3 genomes AF: 0.00101 AC: 154 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00292

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

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: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000251 AC: 63 AN: 251414 AF XY: 0.000191

Gnomad AFR exome AF: 0.00252

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000107 AC: 156 AN: 1461878 Hom.: 0 Cov.: 32 AF XY: 0.0000866 AC XY: 63 AN XY: 727244

African (AFR) AF: 0.00275 AC: 92 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44724

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

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112002

Other (OTH) AF: 0.000414 AC: 25 AN: 60396

GnomAD4 genome AF: 0.00104 AC: 159 AN: 152292 Hom.: 0 Cov.: 32 AF XY: 0.00105 AC XY: 78 AN XY: 74474

African (AFR) AF: 0.00303 AC: 126 AN: 41568

American (AMR) AF: 0.00196 AC: 30 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68022

Other (OTH) AF: 0.00143 AC: 3 AN: 2104

Alfa AF: 0.000377 Hom.: 0

Bravo AF: 0.00136

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000272 AC: 33

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	15
DANN	Benign	0.38
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.18	T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.0042	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-1.3	N
PhyloP100		3.2
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.065
Sift	Benign	0.69	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.59
MPC		0.43
ClinPred		0.0010	T
GERP RS		3.6
Varity_R		0.028
gMVP		0.26
Mutation Taster		=96/4	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: rs140875148; hg19: chr14-95562347;