14-95099771-CAA-CAAAA

Variant names:

• chr14-95099771-C-CAA
• rs1555368535
• NM_177438.3:c.4206+7_4206+8dupTT

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The NM_177438.3(DICER1):​c.4206+7_4206+8dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0484 in 26,818 control chromosomes in the GnomAD database, including 29 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.048 (29 hom., cov: 30)
  • Exomes 𝑓: 0.018 (101 hom.)
  • Failed GnomAD Quality Control
• Consequence: DICER1 NM_177438.3 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: -0.425
• 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 -9 ACMG points.

• BP6: Variant 14-95099771-C-CAA is Benign according to our data. Variant chr14-95099771-C-CAA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 221129.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0589 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+7_4206+8dupTT		splice_region intron	N/A	NP_803187.1	Q9UPY3-1
	DICER1	NM_001271282.3		c.4206+7_4206+8dupTT		splice_region intron	N/A	NP_001258211.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.4206+7_4206+8dupTT		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+9insTT		splice_region intron	N/A	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.4206+8_4206+9insTT		splice_region intron	N/A	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000527414.5	TSL:1	c.4206+8_4206+9insTT		splice_region intron	N/A	ENSP00000435681.1	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.0482 AC: 1289 AN: 26738 Hom.: 29 Cov.: 30

Gnomad AFR AF: 0.0619

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0344

Gnomad ASJ AF: 0.0410

Gnomad EAS AF: 0.0155

Gnomad SAS AF: 0.0371

Gnomad FIN AF: 0.00540

Gnomad MID AF: 0.114

Gnomad NFE AF: 0.0394

Gnomad OTH AF: 0.0461

GnomAD2 exomes AF: 0.00964 AC: 1645 AN: 170614 AF XY: 0.00887

Gnomad AFR exome AF: 0.0358

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0117

Gnomad EAS exome AF: 0.00212

Gnomad FIN exome AF: 0.00414

Gnomad NFE exome AF: 0.00623

Gnomad OTH exome AF: 0.0115

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0183 AC: 4990 AN: 272402 Hom.: 101 Cov.: 34 AF XY: 0.0185 AC XY: 2470 AN XY: 133590

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

African (AFR) AF: 0.0546 AC: 693 AN: 12700

American (AMR) AF: 0.0487 AC: 240 AN: 4924

Ashkenazi Jewish (ASJ) AF: 0.0272 AC: 123 AN: 4516

East Asian (EAS) AF: 0.0183 AC: 44 AN: 2402

South Asian (SAS) AF: 0.0266 AC: 381 AN: 14336

European-Finnish (FIN) AF: 0.00322 AC: 29 AN: 9006

Middle Eastern (MID) AF: 0.0375 AC: 59 AN: 1574

European-Non Finnish (NFE) AF: 0.0148 AC: 3128 AN: 211356

Other (OTH) AF: 0.0253 AC: 293 AN: 11588

⚠️ 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: 0.0484 AC: 1299 AN: 26818 Hom.: 29 Cov.: 30 AF XY: 0.0445 AC XY: 580 AN XY: 13022

African (AFR) AF: 0.0624 AC: 862 AN: 13822

American (AMR) AF: 0.0344 AC: 72 AN: 2092

Ashkenazi Jewish (ASJ) AF: 0.0410 AC: 22 AN: 536

East Asian (EAS) AF: 0.0155 AC: 3 AN: 194

South Asian (SAS) AF: 0.0367 AC: 25 AN: 682

European-Finnish (FIN) AF: 0.00540 AC: 10 AN: 1852

Middle Eastern (MID) AF: 0.100 AC: 7 AN: 70

European-Non Finnish (NFE) AF: 0.0394 AC: 279 AN: 7080

Other (OTH) AF: 0.0452 AC: 19 AN: 420

Alfa AF: 0.00806 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not specified (4)
-	-	2	DICER1-related tumor predisposition (2)
-	-	1	Pleuropulmonary blastoma (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

Other links and lift over

dbSNP: rs1555368535; hg19: chr14-95566108; COSMIC: COSV100601699; COSMIC: COSV100601699;