14-95099771-C-CACACACAA

Variant names:

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

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+8_4206+9insTTGTGTGT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 26,840 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Benign (★★). The gene DICER1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.017 (13 hom., cov: 30)
  • Exomes 𝑓: 0.0020 (15 hom.)
  • Failed GnomAD Quality Control
• Consequence: DICER1 NM_177438.3 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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

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 14-95099771-C-CACACACAA is Benign according to our data. Variant chr14-95099771-C-CACACACAA is described in ClinVar as Benign. ClinVar VariationId is 220996.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 = 0.0166 (445/26840) while in subpopulation AFR AF = 0.0304 (421/13832). AF 95% confidence interval is 0.028. There are 13 homozygotes in GnomAd4. There are 217 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High AC in GnomAd4 at 445 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+9insTTGTGTGT		splice_region intron	N/A	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.4206+8_4206+9insTTGTGTGT		splice_region intron	N/A	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.4206+8_4206+9insTTGTGTGT		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+9insTTGTGTGT		splice_region intron	N/A	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.4206+8_4206+9insTTGTGTGT		splice_region intron	N/A	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.4206+8_4206+9insTTGTGTGT		splice_region intron	N/A	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 447 AN: 26760 Hom.: 13 Cov.: 30

Gnomad AFR AF: 0.0307

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00667

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: 0.00127

Gnomad OTH AF: 0.00243

GnomAD2 exomes AF: 0.00158 AC: 269 AN: 170614 AF XY: 0.00140

Gnomad AFR exome AF: 0.0194

Gnomad AMR exome AF: 0.00114

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000787

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000180

Gnomad OTH exome AF: 0.000941

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00202 AC: 554 AN: 274648 Hom.: 15 Cov.: 34 AF XY: 0.00182 AC XY: 245 AN XY: 134614

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

African (AFR) AF: 0.0304 AC: 390 AN: 12818

American (AMR) AF: 0.00804 AC: 40 AN: 4978

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

East Asian (EAS) AF: 0.000413 AC: 1 AN: 2420

South Asian (SAS) AF: 0.000207 AC: 3 AN: 14514

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

Middle Eastern (MID) AF: 0.00314 AC: 5 AN: 1590

European-Non Finnish (NFE) AF: 0.000324 AC: 69 AN: 213012

Other (OTH) AF: 0.00393 AC: 46 AN: 11702

⚠️ 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: 0.0166 AC: 445 AN: 26840 Hom.: 13 Cov.: 30 AF XY: 0.0166 AC XY: 217 AN XY: 13038

African (AFR) AF: 0.0304 AC: 421 AN: 13832

American (AMR) AF: 0.00669 AC: 14 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: 0.00127 AC: 9 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
-	-	2	not specified (2)
-	-	1	DICER1-related tumor predisposition (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.42
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs763704682;

hg19: chr14-95566108;