rs774228906

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152383.5(DIS3L2):c.1826G>A(p.Arg609Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000534 in 1,459,512 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R609W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.84

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DIS3L2	NM_152383.5 linkuse as main transcript	c.1826G>A	p.Arg609Gln	missense_variant	15/21	ENST00000325385.12
DIS3L2	NM_001257281.2 linkuse as main transcript	c.1582-13446G>A		intron_variant
DIS3L2	NR_046476.2 linkuse as main transcript	n.1899G>A		non_coding_transcript_exon_variant	15/21
DIS3L2	NR_046477.2 linkuse as main transcript	n.1878G>A		non_coding_transcript_exon_variant	14/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L2	ENST00000325385.12 linkuse as main transcript	c.1826G>A	p.Arg609Gln	missense_variant	15/21	5	NM_152383.5	P1	Q8IYB7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

247326

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134504

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000446

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000534

AC:

AN:

1459512

Hom.:

Cov.:

AF XY:

0.0000331

AC XY:

AN XY:

726070

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000684

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000248

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Perlman syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 09, 2023

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 609 of the DIS3L2 protein (p.Arg609Gln). This variant is present in population databases (rs774228906, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. ClinVar contains an entry for this variant (Variation ID: 410728). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DIS3L2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

May 19, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.0082

BayesDel_noAF

Benign

-0.12

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.22

T;T;T

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;.;D

M_CAP

Benign

0.030

MetaRNN

Uncertain

0.47

T;T;T

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.1

M;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.4

N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.020

D;D;T

Sift4G

Benign

0.081

T;T;T

Polyphen

0.80

P;P;.

Vest4

0.79

MutPred

0.53

Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;

MVP

0.13

MPC

0.84

ClinPred

0.78

GERP RS

4.5

Varity_R

0.65

gMVP

0.80

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