Genetic Variant DIS3L2:p.Arg794Leu (chr2-232334722-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_152383.5(DIS3L2):c.2381G>T(p.Arg794Leu) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R794H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.95

Publications

1 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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

DIS3L2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152383.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIS3L2	NM_152383.5	MANE Select	c.2381G>T	p.Arg794Leu	missense	Exon 19 of 21	NP_689596.4
DIS3L2	NM_001257281.2		c.1582-8623G>T		intron	N/A	NP_001244210.1	Q8IYB7-3
DIS3L2	NR_046476.2		n.2454G>T		non_coding_transcript_exon	Exon 19 of 21

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.2381G>T	p.Arg794Leu	missense	Exon 19 of 21	ENSP00000315569.7	Q8IYB7-1
DIS3L2	ENST00000390005.9	TSL:1	n.*448G>T		non_coding_transcript_exon	Exon 19 of 21	ENSP00000374655.5	Q8IYB7-2
DIS3L2	ENST00000445090.5	TSL:1	n.*1537G>T		non_coding_transcript_exon	Exon 18 of 19	ENSP00000388999.1	Q8IYB7-4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1453266

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722402

African (AFR)

AF:

0.00

AC:

AN:

33222

American (AMR)

AF:

0.00

AC:

AN:

44012

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26006

East Asian (EAS)

AF:

0.00

AC:

AN:

39136

South Asian (SAS)

AF:

0.00

AC:

AN:

84994

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52038

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5298

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108540

Other (OTH)

AF:

0.00

AC:

AN:

60020

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Perlman syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.96

MutationAssessor

Pathogenic

3.3

PhyloP100

8.0

PrimateAI

Uncertain

0.68

PROVEAN

Pathogenic

-6.0

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0050

Polyphen

0.49

Vest4

0.92

MutPred

0.67

Loss of MoRF binding (P = 0.0191)

MVP

0.23

MPC

0.89

ClinPred

0.99

GERP RS

4.1

PromoterAI

-0.014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.82

gMVP

0.86

Mutation Taster

=61/39

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over