rs748368348

Variant names:

• chr14-95099760-ACACACACACAC-A
• rs748368348
• NM_177438.3:c.4206+9_4206+19delGTGTGTGTGTG

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+9_4206+19delGTGTGTGTGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0907 in 1,580,912 control chromosomes in the GnomAD database, including 3,100 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.092 (976 hom., cov: 0)
  • Exomes 𝑓: 0.090 (2124 hom.)
• Consequence: DICER1 NM_177438.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.918
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 14-95099760-ACACACACACAC-A is Benign according to our data. Variant chr14-95099760-ACACACACACAC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 477187.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.355 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+9_4206+19delGTGTGTGTGTG		intron	N/A	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.4206+9_4206+19delGTGTGTGTGTG		intron	N/A	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.4206+9_4206+19delGTGTGTGTGTG		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+9_4206+19delGTGTGTGTGTG		intron	N/A	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.4206+9_4206+19delGTGTGTGTGTG		intron	N/A	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.4206+9_4206+19delGTGTGTGTGTG		intron	N/A	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.0922 AC: 13768 AN: 149290 Hom.: 974 Cov.: 0

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.144

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.139

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0769

Gnomad NFE AF: 0.0875

Gnomad OTH AF: 0.0902

GnomAD2 exomes AF: 0.0598 AC: 13933 AN: 233034 AF XY: 0.0594

Gnomad AFR exome AF: 0.0215

Gnomad AMR exome AF: 0.0679

Gnomad ASJ exome AF: 0.0461

Gnomad EAS exome AF: 0.177

Gnomad FIN exome AF: 0.0553

Gnomad NFE exome AF: 0.0434

Gnomad OTH exome AF: 0.0494

GnomAD4 exome AF: 0.0905 AC: 129542 AN: 1431512 Hom.: 2124 AF XY: 0.0913 AC XY: 65000 AN XY: 711920

African (AFR) AF: 0.0305 AC: 963 AN: 31622

American (AMR) AF: 0.129 AC: 5587 AN: 43358

Ashkenazi Jewish (ASJ) AF: 0.0871 AC: 2234 AN: 25650

East Asian (EAS) AF: 0.330 AC: 12676 AN: 38384

South Asian (SAS) AF: 0.125 AC: 10445 AN: 83820

European-Finnish (FIN) AF: 0.0890 AC: 4376 AN: 49170

Middle Eastern (MID) AF: 0.0920 AC: 519 AN: 5644

European-Non Finnish (NFE) AF: 0.0797 AC: 87192 AN: 1094676

Other (OTH) AF: 0.0938 AC: 5550 AN: 59188

GnomAD4 genome AF: 0.0922 AC: 13770 AN: 149400 Hom.: 976 Cov.: 0 AF XY: 0.0985 AC XY: 7183 AN XY: 72954

African (AFR) AF: 0.0363 AC: 1430 AN: 39420

American (AMR) AF: 0.144 AC: 2178 AN: 15110

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 364 AN: 3454

East Asian (EAS) AF: 0.369 AC: 1890 AN: 5122

South Asian (SAS) AF: 0.139 AC: 664 AN: 4778

European-Finnish (FIN) AF: 0.104 AC: 1082 AN: 10430

Middle Eastern (MID) AF: 0.0793 AC: 23 AN: 290

European-Non Finnish (NFE) AF: 0.0875 AC: 5931 AN: 67800

Other (OTH) AF: 0.0893 AC: 186 AN: 2084

Alfa AF: 0.108 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	DICER1-related tumor predisposition (1)
-	-	1	Hereditary cancer-predisposing syndrome (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: rs748368348; hg19: chr14-95566097; COSMIC: COSV58616789; COSMIC: COSV58616789;