NM_177438.3:c.4206+11delG

Variant names:

• chr14-95099768-AC-A
• rs58202892
• NM_177438.3:c.4206+11delG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_177438.3(DICER1):​c.4206+11delG variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★). The gene DICER1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.22 (3478 hom., cov: 0)
  • Exomes 𝑓: 0.13 (3819 hom.)
  • Failed GnomAD Quality Control
• Consequence: DICER1 NM_177438.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.185
• 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

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

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 14-95099768-AC-A is Benign according to our data. Variant chr14-95099768-AC-A is described in ClinVar as Benign. ClinVar VariationId is 477182.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.36 is higher than 0.05.

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+11delG		intron	N/A	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.4206+11delG		intron	N/A	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.4206+11delG		intron	N/A	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.4206+11delG		intron	N/A	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.4206+11delG		intron	N/A	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.4206+11delG		intron	N/A	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.215 AC: 29416 AN: 136650 Hom.: 3474 Cov.: 0

Gnomad AFR AF: 0.365

Gnomad AMI AF: 0.110

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.257

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.178

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.200

GnomAD2 exomes AF: 0.0101 AC: 2092 AN: 207618 AF XY: 0.00921

Gnomad AFR exome AF: 0.0343

Gnomad AMR exome AF: 0.00920

Gnomad ASJ exome AF: 0.00661

Gnomad EAS exome AF: 0.00658

Gnomad FIN exome AF: 0.00783

Gnomad NFE exome AF: 0.00889

Gnomad OTH exome AF: 0.00813

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.133 AC: 169683 AN: 1273308 Hom.: 3819 Cov.: 0 AF XY: 0.134 AC XY: 84536 AN XY: 631648

African (AFR) AF: 0.290 AC: 7981 AN: 27552

American (AMR) AF: 0.215 AC: 7961 AN: 36988

Ashkenazi Jewish (ASJ) AF: 0.117 AC: 2610 AN: 22292

East Asian (EAS) AF: 0.164 AC: 4716 AN: 28678

South Asian (SAS) AF: 0.196 AC: 13998 AN: 71450

European-Finnish (FIN) AF: 0.128 AC: 5312 AN: 41604

Middle Eastern (MID) AF: 0.142 AC: 684 AN: 4830

European-Non Finnish (NFE) AF: 0.120 AC: 118929 AN: 987666

Other (OTH) AF: 0.143 AC: 7492 AN: 52248

GnomAD4 genome AF: 0.215 AC: 29450 AN: 136746 Hom.: 3478 Cov.: 0 AF XY: 0.216 AC XY: 14328 AN XY: 66340

African (AFR) AF: 0.365 AC: 13101 AN: 35900

American (AMR) AF: 0.208 AC: 2828 AN: 13624

Ashkenazi Jewish (ASJ) AF: 0.140 AC: 442 AN: 3166

East Asian (EAS) AF: 0.191 AC: 785 AN: 4100

South Asian (SAS) AF: 0.257 AC: 1090 AN: 4238

European-Finnish (FIN) AF: 0.152 AC: 1398 AN: 9218

Middle Eastern (MID) AF: 0.173 AC: 46 AN: 266

European-Non Finnish (NFE) AF: 0.146 AC: 9281 AN: 63454

Other (OTH) AF: 0.201 AC: 383 AN: 1904

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	DICER1-related tumor predisposition (1)
-	-	1	Euthyroid goiter;C1266144:Pleuropulmonary blastoma;C1867234:Rhabdomyosarcoma, embryonal, 2;C4748924:Global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs58202892; hg19: chr14-95566105;