dbSNP rs1553539264: DIS3L2:p.Thr432Ala (chr2-232238622-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

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

The NM_152383.5(DIS3L2):c.1294A>G(p.Thr432Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T432T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.65

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:

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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, 0.964

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
DIS3L2	NM_152383.5 link	c.1294A>G	p.Thr432Ala	missense_variant	Exon 11 of 21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2 link	c.1294A>G	p.Thr432Ala	missense_variant	Exon 11 of 14		NP_001244210.1
DIS3L2	NR_046476.2 link	n.1440A>G		non_coding_transcript_exon_variant	Exon 11 of 21
DIS3L2	NR_046477.2 link	n.1416A>G		non_coding_transcript_exon_variant	Exon 10 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12 link	c.1294A>G	p.Thr432Ala	missense_variant	Exon 11 of 21	5	NM_152383.5	ENSP00000315569.7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Perlman syndrome

Uncertain:1

Nov 16, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with DIS3L2-related disease. ClinVar contains an entry for this variant (Variation ID:¬†463056). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with alanine at codon 432 of the DIS3L2 protein (p.Thr432Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

.;T;T;T

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;.;D

M_CAP

Benign

0.075

MetaRNN

Pathogenic

0.96

D;D;D;D

MetaSVM

Uncertain

0.15

MutationAssessor

Pathogenic

3.2

M;M;M;.

PhyloP100

8.7

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-4.3

D;D;D;D

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0040

D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.93

MutPred

0.89

Loss of phosphorylation at T432 (P = 0.0773);Loss of phosphorylation at T432 (P = 0.0773);Loss of phosphorylation at T432 (P = 0.0773);.;

MVP

0.43

MPC

0.82

ClinPred

1.0

GERP RS

5.7

Varity_R

0.82

gMVP

0.80

Mutation Taster

=62/38

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over