rs140969547

Positions:

• chr14-95137908-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_177438.3(DICER1):​c.-45-4405C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00983 in 154,818 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0099 (21 hom., cov: 31)
  • Exomes 𝑓: 0.0083 (0 hom.)
• Consequence: DICER1 NM_177438.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.0310

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 14-95137908-G-A is Benign according to our data. Variant chr14-95137908-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 402593.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00986 (1501/152302) while in subpopulation NFE AF= 0.0117 (797/68020). AF 95% confidence interval is 0.011. There are 21 homozygotes in gnomad4. There are 813 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1501 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DICER1	NM_177438.3	c.-45-4405C>T		intron_variant		ENST00000343455.8	NP_803187.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DICER1	ENST00000343455.8	c.-45-4405C>T		intron_variant		1	NM_177438.3	ENSP00000343745.3

Frequencies

GnomAD3 genomes AF: 0.00986 AC: 1501 AN: 152184 Hom.: 21 Cov.: 31

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0493

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0117

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00903 AC: 43 AN: 4764 Hom.: 0 AF XY: 0.0111 AC XY: 27 AN XY: 2438

Gnomad AFR exome AF: 0.00562

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00714

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad NFE exome AF: 0.00974

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00835 AC: 21 AN: 2516 Hom.: 0 Cov.: 0 AF XY: 0.0116 AC XY: 15 AN XY: 1294

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0457

Gnomad4 NFE exome AF: 0.0106

Gnomad4 OTH exome AF: 0.00515

GnomAD4 genome AF: 0.00986 AC: 1501 AN: 152302 Hom.: 21 Cov.: 31 AF XY: 0.0109 AC XY: 813 AN XY: 74476

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0493

Gnomad4 NFE AF: 0.0117

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.0125 Hom.: 3

Bravo AF: 0.00600

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	DICER1: BS1, BS2 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: classification based on MAF and lack of conservation at that base -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs140969547; hg19: chr14-95604245;