dbSNP rs202059499: DIS3L2:p.Pro88Gln (chr2-232024329-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_152383.5(DIS3L2):c.263C>A(p.Pro88Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000692 in 1,445,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P88L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

DIS3L2
NM_152383.5 missense, splice_region

Scores

Splicing: ADA: 0.5333

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.14

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.38399655).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5 link	c.263C>A	p.Pro88Gln	missense_variant, splice_region_variant	Exon 4 of 21	ENST00000325385.12	NP_689596.4	Q8IYB7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12 link	c.263C>A	p.Pro88Gln	missense_variant, splice_region_variant	Exon 4 of 21	5	NM_152383.5	ENSP00000315569.7		Q8IYB7-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1445256

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

718756

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32764

American (AMR)

AF:

0.00

AC:

AN:

42768

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25906

East Asian (EAS)

AF:

0.00

AC:

AN:

39266

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82332

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53312

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1103348

Other (OTH)

AF:

0.00

AC:

AN:

59840

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.018

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.12

.;T;.;T;T

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D;.;D;.

M_CAP

Benign

0.038

MetaRNN

Benign

0.38

T;T;T;T;T

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.3

M;M;M;.;M

PhyloP100

6.1

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-4.0

D;D;D;D;D

REVEL

Benign

0.21

Sift

Uncertain

0.018

D;D;D;D;D

Sift4G

Benign

0.12

T;D;D;D;D

Polyphen

0.99, 0.97

.;D;D;.;D

Vest4

0.73

MutPred

0.31

Loss of glycosylation at S87 (P = 0.0891);Loss of glycosylation at S87 (P = 0.0891);Loss of glycosylation at S87 (P = 0.0891);Loss of glycosylation at S87 (P = 0.0891);Loss of glycosylation at S87 (P = 0.0891);

MVP

0.21

MPC

0.68

ClinPred

0.99

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.41

gMVP

0.45

Mutation Taster

=33/67

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.53

dbscSNV1_RF

Benign

0.52

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

Computational scores

Splicing

Publications

Other links and lift over