chr14-95099771-C-CACACACACACAA

Variant names:

• chr14-95099771-C-CACACACACACAA
• rs763704682
• NM_177438.3:c.4206+8_4206+9insTTGTGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_177438.3(DICER1):​c.4206+8_4206+9insTTGTGTGTGTGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00779 in 26,832 control chromosomes in the GnomAD database, including 8 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0078 (8 hom., cov: 30)
  • Exomes 𝑓: 0.00036 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: DICER1 NM_177438.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.425
• 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

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 14-95099771-C-CACACACACACAA is Benign according to our data. Variant chr14-95099771-C-CACACACACACAA is described in ClinVar as Benign. ClinVar VariationId is 242103.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00779 (209/26832) while in subpopulation AFR AF = 0.0149 (206/13824). AF 95% confidence interval is 0.0132. There are 8 homozygotes in GnomAd4. There are 90 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 209 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+8_4206+9insTTGTGTGTGTGT		splice_region intron	N/A	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.4206+8_4206+9insTTGTGTGTGTGT		splice_region intron	N/A	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.4206+8_4206+9insTTGTGTGTGTGT		splice_region 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+8_4206+9insTTGTGTGTGTGT		splice_region intron	N/A	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.4206+8_4206+9insTTGTGTGTGTGT		splice_region intron	N/A	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.4206+8_4206+9insTTGTGTGTGTGT		splice_region intron	N/A	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.00774 AC: 207 AN: 26752 Hom.: 7 Cov.: 30

Gnomad AFR AF: 0.0148

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000953

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: 0.00

Gnomad OTH AF: 0.00243

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.000360 AC: 99 AN: 274838 Hom.: 2 Cov.: 34 AF XY: 0.000349 AC XY: 47 AN XY: 134690

African (AFR) AF: 0.00658 AC: 85 AN: 12922

American (AMR) AF: 0.00100 AC: 5 AN: 4986

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 4588

East Asian (EAS) AF: 0.00 AC: 0 AN: 2420

South Asian (SAS) AF: 0.00 AC: 0 AN: 14514

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1588

European-Non Finnish (NFE) AF: 0.0000141 AC: 3 AN: 213062

Other (OTH) AF: 0.000511 AC: 6 AN: 11732

GnomAD4 genome AF: 0.00779 AC: 209 AN: 26832 Hom.: 8 Cov.: 30 AF XY: 0.00691 AC XY: 90 AN XY: 13034

African (AFR) AF: 0.0149 AC: 206 AN: 13824

American (AMR) AF: 0.000955 AC: 2 AN: 2094

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 536

East Asian (EAS) AF: 0.00 AC: 0 AN: 194

South Asian (SAS) AF: 0.00 AC: 0 AN: 684

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 70

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 7088

Other (OTH) AF: 0.00238 AC: 1 AN: 420

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.42

Splicing

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

Other links and lift over

dbSNP: rs763704682; hg19: chr14-95566108;