rs754008215
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_152383.5(DIS3L2):c.1163G>A(p.Arg388Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,613,566 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000082 ( 0 hom. )
Consequence
DIS3L2
NM_152383.5 missense
NM_152383.5 missense
Scores
2
8
8
Clinical Significance
Conservation
PhyloP100: 2.79
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 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DIS3L2 | NM_152383.5 | c.1163G>A | p.Arg388Gln | missense_variant | 10/21 | ENST00000325385.12 | |
DIS3L2 | NM_001257281.2 | c.1163G>A | p.Arg388Gln | missense_variant | 10/14 | ||
DIS3L2 | NR_046476.2 | n.1309G>A | non_coding_transcript_exon_variant | 10/21 | |||
DIS3L2 | NR_046477.2 | n.1285G>A | non_coding_transcript_exon_variant | 9/19 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DIS3L2 | ENST00000325385.12 | c.1163G>A | p.Arg388Gln | missense_variant | 10/21 | 5 | NM_152383.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
2
AN:
152164
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000240 AC: 6AN: 249512Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135372
GnomAD3 exomes
AF:
AC:
6
AN:
249512
Hom.:
AF XY:
AC XY:
3
AN XY:
135372
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000821 AC: 12AN: 1461402Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727004
GnomAD4 exome
AF:
AC:
12
AN:
1461402
Hom.:
Cov.:
30
AF XY:
AC XY:
3
AN XY:
727004
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74338
GnomAD4 genome
?
AF:
AC:
2
AN:
152164
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
74338
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Bravo
AF:
ExAC
?
AF:
AC:
3
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 02, 2021 | The c.1163G>A (p.R388Q) alteration is located in exon 10 (coding exon 9) of the DIS3L2 gene. This alteration results from a G to A substitution at nucleotide position 1163, causing the arginine (R) at amino acid position 388 to be replaced by a glutamine (Q). The p.R388Q alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
DIS3L2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 28, 2022 | The DIS3L2 c.1163G>A variant is predicted to result in the amino acid substitution p.Arg388Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.015% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-233075074-G-A). This variant is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/580061). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Perlman syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 388 of the DIS3L2 protein (p.Arg388Gln). This variant is present in population databases (rs754008215, gnomAD 0.02%). 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: 580061). 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 with a negative predictive value of 80%. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Pathogenic
D;D;.;D
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Benign
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
0.97
.;D;D;.
Vest4
MutPred
Loss of phosphorylation at S385 (P = 0.1132);Loss of phosphorylation at S385 (P = 0.1132);Loss of phosphorylation at S385 (P = 0.1132);.;
MVP
MPC
0.87
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at