rs148474013

Positions:

chr2-232263229-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_152383.5(DIS3L2):c.1448G>A(p.Arg483Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00561 in 1,614,180 control chromosomes in the GnomAD database, including 136 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R483G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0085 ( 23 hom., cov: 33)

Exomes 𝑓: 0.0053 ( 113 hom. )

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 5.43

Variant links:

Genes affected

DIS3L2 (HGNC:28648): (DIS3 like 3'-5' exoribonuclease 2) The protein encoded by this gene is similar in sequence to 3'/5' exonucleolytic subunits of the RNA exosome. The exosome is a large multimeric ribonucleotide complex responsible for degrading various RNA substrates. Several transcript variants, some protein-coding and some not, have been found for this gene. [provided by RefSeq, Mar 2012]

DIS3L2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0058790445).

BP6

Variant 2-232263229-G-A is Benign according to our data. Variant chr2-232263229-G-A is described in ClinVar as [Benign]. Clinvar id is 262630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-232263229-G-A is described in Lovd as [Benign]. Variant chr2-232263229-G-A is described in Lovd as [Likely_benign].

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0543 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DIS3L2	NM_152383.5 linkuse as main transcript	c.1448G>A	p.Arg483Gln	missense_variant	13/21	ENST00000325385.12
DIS3L2	NM_001257281.2 linkuse as main transcript	c.1448G>A	p.Arg483Gln	missense_variant	13/14
DIS3L2	NR_046476.2 linkuse as main transcript	n.1594G>A		non_coding_transcript_exon_variant	13/21
DIS3L2	NR_046477.2 linkuse as main transcript	n.1570G>A		non_coding_transcript_exon_variant	12/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L2	ENST00000325385.12 linkuse as main transcript	c.1448G>A	p.Arg483Gln	missense_variant	13/21	5	NM_152383.5	P1	Q8IYB7-1

Frequencies

GnomAD3 genomes

AF:

0.00848

AC:

1290

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00147

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0485

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.0162

Gnomad SAS

AF:

0.0168

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00226

Gnomad OTH

AF:

0.00813

GnomAD3 exomes

AF:

0.0139

AC:

3456

AN:

249342

Hom.:

AF XY:

0.0127

AC XY:

1713

AN XY:

135268

show subpopulations

Gnomad AFR exome

AF:

0.00149

Gnomad AMR exome

AF:

0.0596

Gnomad ASJ exome

AF:

0.00139

Gnomad EAS exome

AF:

0.0180

Gnomad SAS exome

AF:

0.0164

Gnomad FIN exome

AF:

0.0120

Gnomad NFE exome

AF:

0.00182

Gnomad OTH exome

AF:

0.0119

GnomAD4 exome

AF:

0.00531

AC:

7761

AN:

1461876

Hom.:

113

Cov.:

AF XY:

0.00549

AC XY:

3996

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.000777

Gnomad4 AMR exome

AF:

0.0562

Gnomad4 ASJ exome

AF:

0.00134

Gnomad4 EAS exome

AF:

0.0132

Gnomad4 SAS exome

AF:

0.0173

Gnomad4 FIN exome

AF:

0.0126

Gnomad4 NFE exome

AF:

0.00196

Gnomad4 OTH exome

AF:

0.00525

GnomAD4 genome

AF:

0.00847

AC:

1290

AN:

152304

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

802

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.00147

Gnomad4 AMR

AF:

0.0484

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.0160

Gnomad4 SAS

AF:

0.0170

Gnomad4 FIN

AF:

0.0139

Gnomad4 NFE

AF:

0.00226

Gnomad4 OTH

AF:

0.00805

Alfa

AF:

0.00291

Hom.:

Bravo

AF:

0.00980

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00103

AC:

ESP6500EA

AF:

0.00216

AC:

ExAC

AF:

0.0113

AC:

1368

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.00234

EpiControl

AF:

0.00178

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Perlman syndrome

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 17, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.26

.;T;T;T

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

D;D;.;D

MetaRNN

Benign

0.0059

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.5

M;M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.38

PROVEAN

Uncertain

-3.6

D;D;D;D

REVEL

Uncertain

0.30

Sift

Pathogenic

0.0

D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.34

MPC

0.58

ClinPred

0.036

GERP RS

4.2

Varity_R

0.86

gMVP

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over