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rs766892626

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_152383.5(DIS3L2):c.1418A>C(p.Glu473Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 152,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 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. E473G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Consequence

DIS3L2
NM_152383.5 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.79
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24494958).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DIS3L2NM_152383.5 linkuse as main transcriptc.1418A>C p.Glu473Ala missense_variant 12/21 ENST00000325385.12
DIS3L2NM_001257281.2 linkuse as main transcriptc.1418A>C p.Glu473Ala missense_variant 12/14
DIS3L2NR_046476.2 linkuse as main transcriptn.1564A>C non_coding_transcript_exon_variant 12/21
DIS3L2NR_046477.2 linkuse as main transcriptn.1540A>C non_coding_transcript_exon_variant 11/19

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DIS3L2ENST00000325385.12 linkuse as main transcriptc.1418A>C p.Glu473Ala missense_variant 12/215 NM_152383.5 P1Q8IYB7-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152220
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152220
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.0000482
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Perlman syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeFeb 03, 2023In 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. 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. ClinVar contains an entry for this variant (Variation ID: 1443698). This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 473 of the DIS3L2 protein (p.Glu473Ala). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.46
Cadd
Benign
19
Dann
Benign
0.96
Eigen
Benign
-0.48
Eigen_PC
Benign
-0.34
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.71
T;T;.;T
M_CAP
Benign
0.017
T
MetaRNN
Benign
0.24
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L;L;L;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Benign
0.23
T
PROVEAN
Uncertain
-3.0
D;D;D;D
REVEL
Benign
0.065
Sift
Benign
0.11
T;D;D;T
Sift4G
Benign
0.090
T;T;T;T
Polyphen
0.014
.;B;B;.
Vest4
0.33
MutPred
0.47
Loss of ubiquitination at K475 (P = 0.0634);Loss of ubiquitination at K475 (P = 0.0634);Loss of ubiquitination at K475 (P = 0.0634);.;
MVP
0.068
MPC
0.42
ClinPred
0.77
D
GERP RS
3.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.29
gMVP
0.55

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.

Other links and lift over

dbSNP: rs766892626; hg19: chr2-233114049; API