NM_177438.3:c.4206+9_4206+15delGTGTGTG

Variant names:

• chr14-95099764-ACACACAC-A
• rs199508452
• NM_177438.3:c.4206+9_4206+15delGTGTGTG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_177438.3(DICER1):​c.4206+9_4206+15delGTGTGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00491 in 1,212,756 control chromosomes in the GnomAD database, including 72 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (10 hom., cov: 0)
  • Exomes 𝑓: 0.0047 (62 hom.)
• Consequence: DICER1 NM_177438.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.918
• Publications: 0 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 -16 ACMG points.

• BP6: Variant 14-95099764-ACACACAC-A is Benign according to our data. Variant chr14-95099764-ACACACAC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 477185.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00678 (812/119826) while in subpopulation AFR AF = 0.0195 (652/33446). AF 95% confidence interval is 0.0183. There are 10 homozygotes in GnomAd4. There are 364 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 812 AD,Unknown gene.

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.4206+9_4206+15delGTGTGTG		intron	N/A	NP_803187.1
	DICER1	NM_001271282.3		c.4206+9_4206+15delGTGTGTG		intron	N/A	NP_001258211.1
	DICER1	NM_001291628.2		c.4206+9_4206+15delGTGTGTG		intron	N/A	NP_001278557.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.4206+9_4206+15delGTGTGTG		intron	N/A	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.4206+9_4206+15delGTGTGTG		intron	N/A	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.4206+9_4206+15delGTGTGTG		intron	N/A	ENSP00000435681.1

Frequencies

GnomAD3 genomes AF: 0.00676 AC: 810 AN: 119750 Hom.: 10 Cov.: 0

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00374

Gnomad ASJ AF: 0.00109

Gnomad EAS AF: 0.00720

Gnomad SAS AF: 0.00505

Gnomad FIN AF: 0.000244

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.00784

GnomAD2 exomes AF: 0.00426 AC: 874 AN: 205036 AF XY: 0.00414

Gnomad AFR exome AF: 0.0125

Gnomad AMR exome AF: 0.00337

Gnomad ASJ exome AF: 0.00445

Gnomad EAS exome AF: 0.00378

Gnomad FIN exome AF: 0.00209

Gnomad NFE exome AF: 0.00380

Gnomad OTH exome AF: 0.00414

GnomAD4 exome AF: 0.00471 AC: 5145 AN: 1092930 Hom.: 62 AF XY: 0.00487 AC XY: 2641 AN XY: 541746

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0216 AC: 553 AN: 25590

American (AMR) AF: 0.00685 AC: 203 AN: 29652

Ashkenazi Jewish (ASJ) AF: 0.00500 AC: 96 AN: 19204

East Asian (EAS) AF: 0.00982 AC: 134 AN: 13646

South Asian (SAS) AF: 0.0109 AC: 646 AN: 59112

European-Finnish (FIN) AF: 0.00408 AC: 147 AN: 36026

Middle Eastern (MID) AF: 0.00523 AC: 22 AN: 4204

European-Non Finnish (NFE) AF: 0.00355 AC: 3056 AN: 861250

Other (OTH) AF: 0.00651 AC: 288 AN: 44246

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00678 AC: 812 AN: 119826 Hom.: 10 Cov.: 0 AF XY: 0.00631 AC XY: 364 AN XY: 57720

African (AFR) AF: 0.0195 AC: 652 AN: 33446

American (AMR) AF: 0.00373 AC: 41 AN: 10984

Ashkenazi Jewish (ASJ) AF: 0.00109 AC: 3 AN: 2762

East Asian (EAS) AF: 0.00725 AC: 15 AN: 2070

South Asian (SAS) AF: 0.00506 AC: 18 AN: 3554

European-Finnish (FIN) AF: 0.000244 AC: 2 AN: 8190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 244

European-Non Finnish (NFE) AF: 0.00121 AC: 68 AN: 56030

Other (OTH) AF: 0.00774 AC: 13 AN: 1680

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	DICER1-related tumor predisposition (2)
-	-	1	Euthyroid goiter (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.92
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199508452; hg19: chr14-95566101;