rs753955550

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_152383.5(DIS3L2):c.1775C>T(p.Ala592Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,393,208 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. A592S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000073 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67

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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5 link	c.1775C>T	p.Ala592Val	missense_variant	Exon 15 of 21	ENST00000325385.12	NP_689596.4	Q8IYB7-1
DIS3L2	NM_001257281.2 link	c.1582-13497C>T		intron_variant	Intron 13 of 13		NP_001244210.1	Q8IYB7-3
DIS3L2	NR_046476.2 link	n.1886-38C>T		intron_variant	Intron 14 of 20
DIS3L2	NR_046477.2 link	n.1862-35C>T		intron_variant	Intron 13 of 18

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12 link	c.1775C>T	p.Ala592Val	missense_variant	Exon 15 of 21	5	NM_152383.5	ENSP00000315569.7		Q8IYB7-1

Frequencies

GnomAD3 genomes

AF:

0.00000728

AC:

AN:

137376

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000155

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000128

AC:

AN:

235236

AF XY:

0.0000156

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000308

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000941

Gnomad OTH exome

AF:

0.000177

GnomAD4 exome

AF:

0.0000167

AC:

AN:

1255832

Hom.:

Cov.:

AF XY:

0.0000145

AC XY:

AN XY:

621772

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27356

American (AMR)

AF:

0.0000266

AC:

AN:

37554

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18512

East Asian (EAS)

AF:

0.00

AC:

AN:

21876

South Asian (SAS)

AF:

0.0000484

AC:

AN:

82730

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36062

Middle Eastern (MID)

AF:

0.000644

AC:

AN:

4656

European-Non Finnish (NFE)

AF:

0.00000918

AC:

AN:

979962

Other (OTH)

AF:

0.0000849

AC:

AN:

47124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000728

AC:

AN:

137376

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

65878

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

37416

American (AMR)

AF:

0.00

AC:

AN:

12880

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3340

East Asian (EAS)

AF:

0.00

AC:

AN:

3972

South Asian (SAS)

AF:

0.00

AC:

AN:

3908

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8110

Middle Eastern (MID)

AF:

0.00

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.0000155

AC:

AN:

64654

Other (OTH)

AF:

0.00

AC:

AN:

1934

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000828

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Perlman syndrome

Uncertain:1

Apr 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 592 of the DIS3L2 protein (p.Ala592Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 463074). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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

Benign

0.32

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Uncertain

-0.080

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

T;T;T

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.88

D;.;D

M_CAP

Benign

0.040

MetaRNN

Uncertain

0.68

D;D;D

MetaSVM

Benign

-0.95

MutationAssessor

Benign

2.0

M;M;.

PhyloP100

7.7

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.017

D;D;D

Sift4G

Uncertain

0.054

T;T;T

Polyphen

0.80

P;P;.

Vest4

0.83

MutPred

0.74

Gain of methylation at K596 (P = 0.0783);Gain of methylation at K596 (P = 0.0783);.;

MVP

0.11

MPC

0.79

ClinPred

0.93

GERP RS

5.3

Varity_R

0.53

gMVP

0.66

Mutation Taster

=50/50

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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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rs753955550

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