rs201719374

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6

The NM_152383.5(DIS3L2):c.1430T>G(p.Leu477Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000712 in 1,614,122 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 7.75

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.048276722).

BP6

Variant 2-232263211-T-G is Benign according to our data. Variant chr2-232263211-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 241960.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5 link	c.1430T>G	p.Leu477Arg	missense_variant	Exon 13 of 21	ENST00000325385.12	NP_689596.4	Q8IYB7-1
DIS3L2	NM_001257281.2 link	c.1430T>G	p.Leu477Arg	missense_variant	Exon 13 of 14		NP_001244210.1	Q8IYB7-3
DIS3L2	NR_046476.2 link	n.1576T>G		non_coding_transcript_exon_variant	Exon 13 of 21
DIS3L2	NR_046477.2 link	n.1552T>G		non_coding_transcript_exon_variant	Exon 12 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12 link	c.1430T>G	p.Leu477Arg	missense_variant	Exon 13 of 21	5	NM_152383.5	ENSP00000315569.7		Q8IYB7-1

Frequencies

GnomAD3 genomes

AF:

0.000217

AC:

AN:

152274

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0296

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:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000602

AC:

AN:

249314

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135256

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000561

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

727210

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.0000683

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000217

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74388

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000116

Hom.:

Bravo

AF:

0.000261

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.0000827

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Perlman syndrome

Uncertain:1Benign:1

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

DIS3L2-related disorder

Uncertain:1

Sep 24, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DIS3L2 c.1430T>G variant is predicted to result in the amino acid substitution p.Leu477Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant has been reported as benign (1) and uncertain (2) in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/241960/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided

Uncertain:1

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.091

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

.;T;T;T

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;.;T

M_CAP

Benign

0.033

MetaRNN

Benign

0.048

T;T;T;T

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.8

L;L;L;.

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.0

D;D;D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0070

D;D;D;D

Sift4G

Uncertain

0.038

D;T;T;D

Polyphen

0.90

.;P;P;.

Vest4

0.86

MutPred

0.62

Gain of MoRF binding (P = 0.0393);Gain of MoRF binding (P = 0.0393);Gain of MoRF binding (P = 0.0393);.;

MVP

0.40

MPC

1.0

ClinPred

0.44

GERP RS

5.0

Varity_R

0.85

gMVP

0.82

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over