rs1224235194

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_152383.5(DIS3L2):c.1756A>G(p.Met586Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000011 in 907,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. M586I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 7.22

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

DIS3L2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5 link	c.1756A>G	p.Met586Val	missense_variant	Exon 15 of 21	ENST00000325385.12	NP_689596.4	Q8IYB7-1
DIS3L2	NM_001257281.2 link	c.1582-13516A>G		intron_variant	Intron 13 of 13		NP_001244210.1	Q8IYB7-3
DIS3L2	NR_046476.2 link	n.1886-57A>G		intron_variant	Intron 14 of 20
DIS3L2	NR_046477.2 link	n.1862-54A>G		intron_variant	Intron 13 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12 link	c.1756A>G	p.Met586Val	missense_variant	Exon 15 of 21	5	NM_152383.5	ENSP00000315569.7		Q8IYB7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000486

AC:

AN:

205756

AF XY:

0.00000884

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000118

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

907418

Hom.:

Cov.:

AF XY:

0.0000132

AC XY:

AN XY:

453858

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19604

American (AMR)

AF:

0.00

AC:

AN:

31484

Ashkenazi Jewish (ASJ)

AF:

0.0000721

AC:

AN:

13870

East Asian (EAS)

AF:

0.00

AC:

AN:

12124

South Asian (SAS)

AF:

0.00

AC:

AN:

71482

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29900

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3706

European-Non Finnish (NFE)

AF:

0.0000130

AC:

AN:

692030

Other (OTH)

AF:

0.00

AC:

AN:

33218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

DIS3L2-related disorder

Uncertain:1

Jul 25, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The DIS3L2 c.1756A>G variant is predicted to result in the amino acid substitution p.Met586Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is classified as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/531925/). 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

Dec 29, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 531925). 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 methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 586 of the DIS3L2 protein (p.Met586Val). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

D;D;T

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;.;D

M_CAP

Uncertain

0.096

MetaRNN

Pathogenic

0.94

D;D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Pathogenic

5.0

H;H;.

PhyloP100

7.2

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.7

D;D;D

REVEL

Uncertain

0.59

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.97

MutPred

0.84

Loss of catalytic residue at V582 (P = 0.0341);Loss of catalytic residue at V582 (P = 0.0341);.;

MVP

0.51

MPC

0.83

ClinPred

1.0

GERP RS

5.3

Varity_R

0.93

gMVP

0.85

Mutation Taster

=35/65

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over