rs775814377

Variant summary

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

The NM_152383.5(DIS3L2):​c.1923T>A​(p.Asn641Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DIS3L2
NM_152383.5 missense, splice_region

Scores

2
17
Splicing: ADA: 0.00004363
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -1.85
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]

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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=0.08399564).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DIS3L2NM_152383.5 linkuse as main transcriptc.1923T>A p.Asn641Lys missense_variant, splice_region_variant 15/21 ENST00000325385.12 NP_689596.4
DIS3L2NM_001257281.2 linkuse as main transcriptc.1582-13349T>A intron_variant NP_001244210.1
DIS3L2NR_046476.2 linkuse as main transcriptn.1996T>A splice_region_variant, non_coding_transcript_exon_variant 15/21
DIS3L2NR_046477.2 linkuse as main transcriptn.1975T>A splice_region_variant, non_coding_transcript_exon_variant 14/19

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DIS3L2ENST00000325385.12 linkuse as main transcriptc.1923T>A p.Asn641Lys missense_variant, splice_region_variant 15/215 NM_152383.5 ENSP00000315569 P1Q8IYB7-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.88e-7
AC:
1
AN:
1453802
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
722504
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.03e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

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 testingLabcorp Genetics (formerly Invitae), LabcorpDec 13, 2019This sequence change replaces asparagine with lysine at codon 641 of the DIS3L2 protein (p.Asn641Lys). The asparagine residue is weakly conserved and there is a moderate physicochemical difference between asparagine and lysine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with DIS3L2-related conditions. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.48
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.57
CADD
Benign
13
DANN
Benign
0.95
DEOGEN2
Benign
0.056
T;T;T
Eigen
Benign
-0.87
Eigen_PC
Benign
-0.89
FATHMM_MKL
Benign
0.19
N
LIST_S2
Uncertain
0.89
D;.;D
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.084
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.1
L;L;.
MutationTaster
Benign
0.71
D;D;D
PrimateAI
Benign
0.45
T
PROVEAN
Benign
-0.85
N;N;N
REVEL
Benign
0.067
Sift
Benign
0.14
T;T;T
Sift4G
Benign
0.88
T;T;T
Polyphen
0.0090
B;B;.
Vest4
0.48
MutPred
0.55
Gain of ubiquitination at N641 (P = 0.0104);Gain of ubiquitination at N641 (P = 0.0104);.;
MVP
0.043
MPC
0.36
ClinPred
0.35
T
GERP RS
-5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.25
gMVP
0.69

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000044
dbscSNV1_RF
Benign
0.010
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: rs775814377; hg19: chr2-233194706; API