rs201733073

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_152383.5(DIS3L2):c.410A>G(p.Tyr137Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000884 in 1,613,924 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00070 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00090 ( 1 hom. )

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7B:3

Conservation

PhyloP100: 0.893

Publications

5 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.019897908).

BP6

Variant 2-232087530-A-G is Benign according to our data. Variant chr2-232087530-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 241980.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000697 (106/152124) while in subpopulation NFE AF = 0.00132 (90/67992). AF 95% confidence interval is 0.0011. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

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.410A>G	p.Tyr137Cys	missense	Exon 6 of 21	NP_689596.4
DIS3L2	NM_001257281.2		c.410A>G	p.Tyr137Cys	missense	Exon 6 of 14	NP_001244210.1	Q8IYB7-3
DIS3L2	NM_001257282.2		c.410A>G	p.Tyr137Cys	missense	Exon 6 of 7	NP_001244211.1	Q8IYB7-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.410A>G	p.Tyr137Cys	missense	Exon 6 of 21	ENSP00000315569.7	Q8IYB7-1
DIS3L2	ENST00000409401.7	TSL:1	c.410A>G	p.Tyr137Cys	missense	Exon 6 of 7	ENSP00000386594.3	Q8IYB7-4
DIS3L2	ENST00000390005.9	TSL:1	n.410A>G		non_coding_transcript_exon	Exon 6 of 21	ENSP00000374655.5	Q8IYB7-2

Frequencies

GnomAD3 genomes

AF:

0.000697

AC:

106

AN:

152006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000945

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00132

Gnomad OTH

AF:

0.000956

GnomAD2 exomes

AF:

0.000714

AC:

178

AN:

249458

AF XY:

0.000754

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.000377

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.000660

GnomAD4 exome

AF:

0.000904

AC:

1321

AN:

1461800

Hom.:

Cov.:

AF XY:

0.000877

AC XY:

638

AN XY:

727204

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33476

American (AMR)

AF:

0.000358

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00111

AC:

1233

AN:

1111964

Other (OTH)

AF:

0.000861

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

142

212

283

354

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

152

190

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000697

AC:

106

AN:

152124

Hom.:

Cov.:

AF XY:

0.000753

AC XY:

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41492

American (AMR)

AF:

0.000458

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.0000945

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00132

AC:

AN:

67992

Other (OTH)

AF:

0.000946

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00121

Hom.:

Bravo

AF:

0.000888

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00157

AC:

ExAC

AF:

0.000778

AC:

EpiCase

AF:

0.00147

EpiControl

AF:

0.00142

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Perlman syndrome (5)

not provided (3)

DIS3L2-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0040

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.76

M_CAP

Benign

0.012

MetaRNN

Benign

0.020

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.9

PhyloP100

0.89

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.84

REVEL

Benign

0.048

Sift

Benign

0.15

Sift4G

Benign

0.17

Polyphen

0.90

Vest4

0.13

MVP

0.068

MPC

0.28

ClinPred

0.013

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.053

gMVP

0.31

Mutation Taster

=93/7

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over