chr14-95099756-ACACACACACACACAC-A

Variant names:

• chr14-95099756-ACACACACACACACAC-A
• rs766236360
• NM_177438.3:c.4206+9_4206+23delGTGTGTGTGTGTGTG

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_177438.3(DICER1):​c.4206+9_4206+23delGTGTGTGTGTGTGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000924 in 1,558,664 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000053 (0 hom., cov: 24)
  • Exomes 𝑓: 0.000097 (0 hom.)
• Consequence: DICER1 NM_177438.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.829
• 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 -12 ACMG points.

• BP6: Variant 14-95099756-ACACACACACACACAC-A is Benign according to our data. Variant chr14-95099756-ACACACACACACACAC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 543700.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 8 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+23delGTGTGTGTGTGTGTG		intron	N/A	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.4206+9_4206+23delGTGTGTGTGTGTGTG		intron	N/A	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.4206+9_4206+23delGTGTGTGTGTGTGTG		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+23delGTGTGTGTGTGTGTG		intron	N/A	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.4206+9_4206+23delGTGTGTGTGTGTGTG		intron	N/A	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.4206+9_4206+23delGTGTGTGTGTGTGTG		intron	N/A	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.0000534 AC: 8 AN: 149894 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000261 AC: 60 AN: 230324 AF XY: 0.000255

Gnomad AFR exome AF: 0.000363

Gnomad AMR exome AF: 0.000460

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000516

Gnomad FIN exome AF: 0.000208

Gnomad NFE exome AF: 0.000140

Gnomad OTH exome AF: 0.000693

GnomAD4 exome AF: 0.0000965 AC: 136 AN: 1408658 Hom.: 0 AF XY: 0.0000984 AC XY: 69 AN XY: 700932

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

African (AFR) AF: 0.000157 AC: 5 AN: 31862

American (AMR) AF: 0.000560 AC: 24 AN: 42820

Ashkenazi Jewish (ASJ) AF: 0.0000396 AC: 1 AN: 25278

East Asian (EAS) AF: 0.000427 AC: 15 AN: 35122

South Asian (SAS) AF: 0.000267 AC: 22 AN: 82508

European-Finnish (FIN) AF: 0.000165 AC: 8 AN: 48408

Middle Eastern (MID) AF: 0.000540 AC: 3 AN: 5554

European-Non Finnish (NFE) AF: 0.0000500 AC: 54 AN: 1078962

Other (OTH) AF: 0.0000688 AC: 4 AN: 58144

⚠️ 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: 0.0000533 AC: 8 AN: 150006 Hom.: 0 Cov.: 24 AF XY: 0.0000682 AC XY: 5 AN XY: 73338

African (AFR) AF: 0.0000252 AC: 1 AN: 39666

American (AMR) AF: 0.0000659 AC: 1 AN: 15186

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67890

Other (OTH) AF: 0.00 AC: 0 AN: 2086

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	DICER1-related disorder (1)
-	-	1	DICER1-related tumor predisposition (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.83
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs766236360; hg19: chr14-95566093;