chr14-95099787-T-C

Variant names:

• chr14-95099787-T-C
• rs139536688
• NM_177438.3:c.4199A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS2 BP4

This summary comes from the ClinGen Evidence Repository: The NM_177438.3:c.4199A>G variant in DICER1 is a missense variant predicted to cause substitution of aspartic acid by glycine at amino acid 1400 (p.Asp1400Gly). This variant has been seen in 40 or more unrelated females without tumors through age 50 in at least one testing laboratory and has been observed in a homozygous state in one healthy individual (BS2; Internal lab contributors). The total allele frequency in gnomAD v4.1.0 is 0.000047 (76/1612760 alleles) with a highest population minor allele frequency of 0.000056 (66/1179824 alleles) in the European (non-Finnish) population (PM2_Supporting, BS1, and BA1 are not met). In silico tools predict no damaging impact of the variant on protein function (REVEL: 0.142; MaxEntScan and SpliceAI: no effect on splicing) (BP4). In summary, this variant meets the criteria to be classified as Likely Benign for DICER1-related tumor predisposition based on the ACMG/AMP criteria applied, as specified by the ClinGen DICER1 VCEP: BS2, BP4. (Bayesian Points: -5; VCEP specifications version 1.3.0; 06/24/2025) LINK:https://erepo.genome.network/evrepo/ui/classification/CA7330935/MONDO:0100216/024

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: DICER1 NM_177438.3 missense
• Clinical Significance: Likely benign reviewed by expert panel U:5 B:4
• Conservation: PhyloP100: 4.54
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• 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.4199A>G	p.Asp1400Gly	missense	Exon 22 of 27	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.4199A>G	p.Asp1400Gly	missense	Exon 22 of 27	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.4199A>G	p.Asp1400Gly	missense	Exon 22 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.4199A>G	p.Asp1400Gly	missense	Exon 22 of 27	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.4199A>G	p.Asp1400Gly	missense	Exon 24 of 29	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.4199A>G	p.Asp1400Gly	missense	Exon 22 of 27	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151580 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000280 AC: 7 AN: 250284 AF XY: 0.0000295

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000500 AC: 73 AN: 1461180 Hom.: 0 Cov.: 34 AF XY: 0.0000523 AC XY: 38 AN XY: 726920

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26120

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

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52934

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

European-Non Finnish (NFE) AF: 0.0000567 AC: 63 AN: 1111896

Other (OTH) AF: 0.0000331 AC: 2 AN: 60366

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151580 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74072

African (AFR) AF: 0.00 AC: 0 AN: 41094

American (AMR) AF: 0.00 AC: 0 AN: 15228

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

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

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000849 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000659 AC: 8

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Uncertain	-0.080
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
Eigen	Benign	0.068
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.18	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.5
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.14
Sift	Benign	0.12	T
Sift4G	Benign	0.45	T
Polyphen		0.017	B
Vest4		0.28
MVP		0.83
MPC		0.78
ClinPred		0.13	T
GERP RS		5.8
Varity_R		0.22
gMVP		0.39
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs139536688; hg19: chr14-95566124;