rs773144954

Variant names:

• chr14-95099754-ACACACACACACACACAC-A
• rs773144954
• NM_177438.3:c.4206+9_4206+25delGTGTGTGTGTGTGTGTG

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_177438.3(DICER1):​c.4206+9_4206+25delGTGTGTGTGTGTGTGTG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000319 in 1,600,720 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 28)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: DICER1 NM_177438.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.445
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 14-95099754-ACACACACACACACACAC-A is Benign according to our data. Variant chr14-95099754-ACACACACACACACACAC-A is described in ClinVar as Benign. ClinVar VariationId is 543696.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	NM_177438.3	MANE Select	c.4206+9_4206+25delGTGTGTGTGTGTGTGTG		intron	N/A	NP_803187.1
	DICER1	NM_001271282.3		c.4206+9_4206+25delGTGTGTGTGTGTGTGTG		intron	N/A	NP_001258211.1
	DICER1	NM_001291628.2		c.4206+9_4206+25delGTGTGTGTGTGTGTGTG		intron	N/A	NP_001278557.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.4206+9_4206+25delGTGTGTGTGTGTGTGTG		intron	N/A	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.4206+9_4206+25delGTGTGTGTGTGTGTGTG		intron	N/A	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.4206+9_4206+25delGTGTGTGTGTGTGTGTG		intron	N/A	ENSP00000435681.1

Frequencies

GnomAD3 genomes AF: 0.0000400 AC: 6 AN: 149968 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000736

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000867 AC: 2 AN: 230580 AF XY: 0.00000795

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000186

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000310 AC: 45 AN: 1450752 Hom.: 0 AF XY: 0.0000235 AC XY: 17 AN XY: 721920

African (AFR) AF: 0.00 AC: 0 AN: 32192

American (AMR) AF: 0.00 AC: 0 AN: 44406

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38802

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85754

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.0000361 AC: 40 AN: 1108458

Other (OTH) AF: 0.0000501 AC: 3 AN: 59934

GnomAD4 genome AF: 0.0000400 AC: 6 AN: 149968 Hom.: 0 Cov.: 28 AF XY: 0.0000682 AC XY: 5 AN XY: 73276

African (AFR) AF: 0.0000253 AC: 1 AN: 39488

American (AMR) AF: 0.00 AC: 0 AN: 15176

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2060

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	DICER1-related tumor predisposition (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.45

Splicing

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

Other links and lift over

dbSNP: rs773144954; hg19: chr14-95566091;