rs6575499

Variant names:

• chr14-95155863-T-C
• rs6575499
• NM_177438.3:c.-46+1367A>G

Your query was ambiguous. Multiple possible variants found:

• chr14-95155863-T-C
• chr14-95155863-T-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_177438.3(DICER1):​c.-46+1367A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.22 in 152,160 control chromosomes in the GnomAD database, including 4,045 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene DICER1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: 𝑓 0.22 (4045 hom., cov: 33)
• Consequence: DICER1 NM_177438.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.94
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.306 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.-46+1367A>G		intron	N/A	NP_803187.1	Q9UPY3-1
	DICER1	NM_001291628.2		c.-42+2068A>G		intron	N/A	NP_001278557.1	Q9UPY3-1
	DICER1	NM_001395677.1		c.-213+1857A>G		intron	N/A	NP_001382606.1	Q9UPY3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	ENST00000343455.8	TSL:1 MANE Select	c.-46+1367A>G		intron	N/A	ENSP00000343745.3	Q9UPY3-1
	DICER1	ENST00000393063.6	TSL:1	c.-213+1367A>G		intron	N/A	ENSP00000376783.1	Q9UPY3-1
	DICER1	ENST00000529720.2	TSL:1	c.-247+1367A>G		intron	N/A	ENSP00000433926.2	Q9UPY3-1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33390 AN: 152042 Hom.: 4036 Cov.: 33

Gnomad AFR AF: 0.311

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.269

Gnomad EAS AF: 0.0412

Gnomad SAS AF: 0.0801

Gnomad FIN AF: 0.195

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.234

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.220 AC: 33437 AN: 152160 Hom.: 4045 Cov.: 33 AF XY: 0.214 AC XY: 15913 AN XY: 74388

African (AFR) AF: 0.311 AC: 12905 AN: 41500

American (AMR) AF: 0.159 AC: 2438 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.269 AC: 935 AN: 3470

East Asian (EAS) AF: 0.0412 AC: 214 AN: 5188

South Asian (SAS) AF: 0.0806 AC: 389 AN: 4828

European-Finnish (FIN) AF: 0.195 AC: 2057 AN: 10574

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.202 AC: 13709 AN: 67988

Other (OTH) AF: 0.234 AC: 494 AN: 2112

Alfa AF: 0.145 Hom.: 353

Bravo AF: 0.223

Asia WGS AF: 0.0790 AC: 275 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.52
DANN	Benign	0.72
PhyloP100		-1.9
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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: rs6575499; hg19: chr14-95622200;