rs746597527

Variant names:

• chr14-95099758-ACACACACACACAC-A
• rs746597527
• NM_177438.3:c.4206+9_4206+21delGTGTGTGTGTGTG

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_030621.4(DICER1):​c.4206+9_4206+21delGTGTGTGTGTGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. 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 0.0019 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0048 (35 hom.)
  • Failed GnomAD Quality Control
• Consequence: DICER1 NM_030621.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.918
• 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 -16 ACMG points.

• BP6: Variant 14-95099758-ACACACACACACAC-A is Benign according to our data. Variant chr14-95099758-ACACACACACACAC-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 477188.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 = 0.00185 (278/149996) while in subpopulation AFR AF = 0.00458 (182/39724). AF 95% confidence interval is 0.00404. There are 0 homozygotes in GnomAd4. There are 144 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 278 AD,Unknown gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030621.4. 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+21delGTGTGTGTGTGTG		intron	N/A	NP_803187.1
	DICER1	NM_001271282.3		c.4206+9_4206+21delGTGTGTGTGTGTG		intron	N/A	NP_001258211.1
	DICER1	NM_001291628.2		c.4206+9_4206+21delGTGTGTGTGTGTG		intron	N/A	NP_001278557.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.4206+9_4206+21delGTGTGTGTGTGTG		intron	N/A	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.4206+9_4206+21delGTGTGTGTGTGTG		intron	N/A	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.4206+9_4206+21delGTGTGTGTGTGTG		intron	N/A	ENSP00000435681.1

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 277 AN: 149888 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00457

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00271

Gnomad SAS AF: 0.000417

Gnomad FIN AF: 0.00352

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000236

Gnomad OTH AF: 0.00290

GnomAD2 exomes AF: 0.00819 AC: 1905 AN: 232686 AF XY: 0.00835

Gnomad AFR exome AF: 0.00475

Gnomad AMR exome AF: 0.00938

Gnomad ASJ exome AF: 0.00609

Gnomad EAS exome AF: 0.0297

Gnomad FIN exome AF: 0.00738

Gnomad NFE exome AF: 0.00465

Gnomad OTH exome AF: 0.00672

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00483 AC: 6974 AN: 1443068 Hom.: 35 AF XY: 0.00510 AC XY: 3660 AN XY: 718046

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

African (AFR) AF: 0.00466 AC: 148 AN: 31748

American (AMR) AF: 0.0114 AC: 500 AN: 44018

Ashkenazi Jewish (ASJ) AF: 0.00416 AC: 108 AN: 25960

East Asian (EAS) AF: 0.0536 AC: 1977 AN: 36880

South Asian (SAS) AF: 0.0101 AC: 863 AN: 85038

European-Finnish (FIN) AF: 0.00792 AC: 393 AN: 49652

Middle Eastern (MID) AF: 0.00353 AC: 20 AN: 5664

European-Non Finnish (NFE) AF: 0.00242 AC: 2673 AN: 1104484

Other (OTH) AF: 0.00490 AC: 292 AN: 59624

⚠️ 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: 0.00185 AC: 278 AN: 149996 Hom.: 0 Cov.: 0 AF XY: 0.00197 AC XY: 144 AN XY: 73270

African (AFR) AF: 0.00458 AC: 182 AN: 39724

American (AMR) AF: 0.00132 AC: 20 AN: 15176

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

East Asian (EAS) AF: 0.00272 AC: 14 AN: 5150

South Asian (SAS) AF: 0.000418 AC: 2 AN: 4790

European-Finnish (FIN) AF: 0.00352 AC: 37 AN: 10510

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000236 AC: 16 AN: 67890

Other (OTH) AF: 0.00288 AC: 6 AN: 2084

Alfa AF: 0.00174 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	DICER1-related tumor predisposition (2)
-	-	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: rs746597527; hg19: chr14-95566095;