NM_152383.5:c.674C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_152383.5(DIS3L2):​c.674C>T​(p.Ser225Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,884 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S225S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

DIS3L2
NM_152383.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.08

Publications

0 publications found
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 Gene-Disease associations (from GenCC):
  • Perlman syndrome
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.042558104).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DIS3L2NM_152383.5 linkc.674C>T p.Ser225Leu missense_variant Exon 7 of 21 ENST00000325385.12 NP_689596.4 Q8IYB7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DIS3L2ENST00000325385.12 linkc.674C>T p.Ser225Leu missense_variant Exon 7 of 21 5 NM_152383.5 ENSP00000315569.7 Q8IYB7-1

Frequencies

GnomAD3 genomes
AF:
0.0000592
AC:
9
AN:
152110
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000384
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
GnomAD2 exomes
AF:
0.0000241
AC:
6
AN:
249098
AF XY:
0.0000148
show subpopulations
Gnomad AFR exome
AF:
0.000129
Gnomad AMR exome
AF:
0.0000291
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000111
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000885
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461656
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727132
show subpopulations
African (AFR)
AF:
0.000149
AC:
5
AN:
33472
American (AMR)
AF:
0.0000224
AC:
1
AN:
44698
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26126
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39676
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86230
European-Finnish (FIN)
AF:
0.0000374
AC:
2
AN:
53414
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000630
AC:
7
AN:
1111884
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60388
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.442
Heterozygous variant carriers
0
1
2
4
5
6
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000591
AC:
9
AN:
152228
Hom.:
0
Cov.:
32
AF XY:
0.0000672
AC XY:
5
AN XY:
74424
show subpopulations
African (AFR)
AF:
0.000169
AC:
7
AN:
41526
American (AMR)
AF:
0.00
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.000385
AC:
2
AN:
5190
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4816
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10598
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68020
Other (OTH)
AF:
0.00
AC:
0
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.464
Heterozygous variant carriers
0
1
2
2
3
4
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.0000656
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000331
AC:
4
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Perlman syndrome Uncertain:2
Oct 23, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 225 of the DIS3L2 protein (p.Ser225Leu). This variant is present in population databases (rs201453807, gnomAD 0.03%). 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: 334932). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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. -

Jan 12, 2018
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.068
BayesDel_addAF
Benign
-0.41
T
BayesDel_noAF
Benign
-0.56
CADD
Benign
18
DANN
Uncertain
1.0
DEOGEN2
Benign
0.019
.;T;.;T
Eigen
Benign
-0.35
Eigen_PC
Benign
-0.34
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.27
T;T;.;.
M_CAP
Benign
0.014
T
MetaRNN
Benign
0.043
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.55
N;N;N;N
PhyloP100
1.1
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-1.8
N;N;N;N
REVEL
Benign
0.052
Sift
Uncertain
0.027
D;D;D;D
Sift4G
Benign
0.078
T;D;D;D
Polyphen
0.074, 0.68
.;B;P;B
Vest4
0.13
MVP
0.15
MPC
0.19
ClinPred
0.077
T
GERP RS
4.4
Varity_R
0.060
gMVP
0.32
Mutation Taster
=87/13
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs201453807; hg19: chr2-232995401; API