14-95096720-C-T

Variant names:

• chr14-95096720-C-T
• rs561542587
• NM_177438.3:c.4207-7G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_030621.4(DICER1):​c.4207-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,597,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: DICER1 NM_030621.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002858
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.824
• 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 14-95096720-C-T is Benign according to our data. Variant chr14-95096720-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 477191.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DICER1	NM_177438.3	MANE Select	c.4207-7G>A		splice_region intron	N/A	NP_803187.1
	DICER1	NM_001271282.3		c.4207-7G>A		splice_region intron	N/A	NP_001258211.1
	DICER1	NM_001291628.2		c.4207-7G>A		splice_region 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.4207-7G>A		splice_region intron	N/A	ENSP00000343745.3
	DICER1	ENST00000393063.6	TSL:1	c.4207-7G>A		splice_region intron	N/A	ENSP00000376783.1
	DICER1	ENST00000527414.5	TSL:1	c.4207-7G>A		splice_region intron	N/A	ENSP00000435681.1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152010 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000725

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: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000375 AC: 8 AN: 213110 AF XY: 0.0000346

Gnomad AFR exome AF: 0.000289

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000994

Gnomad NFE exome AF: 0.0000111

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 20 AN: 1444986 Hom.: 0 Cov.: 31 AF XY: 0.0000111 AC XY: 8 AN XY: 717652

African (AFR) AF: 0.000153 AC: 5 AN: 32732

American (AMR) AF: 0.0000236 AC: 1 AN: 42300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25914

East Asian (EAS) AF: 0.00 AC: 0 AN: 38528

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84300

European-Finnish (FIN) AF: 0.0000760 AC: 4 AN: 52616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000725 AC: 8 AN: 1103126

Other (OTH) AF: 0.0000167 AC: 1 AN: 59718

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74340

African (AFR) AF: 0.0000723 AC: 3 AN: 41510

American (AMR) AF: 0.00 AC: 0 AN: 15292

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

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

European-Finnish (FIN) AF: 0.0000946 AC: 1 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.0000540 Hom.: 0

Bravo AF: 0.0000378

ClinVar

ClinVar submissions as Germline

Significance: Likely 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
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.0
DANN	Benign	0.53
PhyloP100		-0.82
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000029
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs561542587; hg19: chr14-95563057;