Genetic Variant DIS3L:p.Arg23Cys (chr15-66293663-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_001143688.3(DIS3L):c.67C>T(p.Arg23Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000994 in 1,428,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

DIS3L
NM_001143688.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.45

Publications

0 publications found

Variant links:

Genes affected

DIS3L (HGNC:28698): (DIS3 like exosome 3'-5' exoribonuclease) The cytoplasmic RNA exosome complex degrades unstable mRNAs and is involved in the regular turnover of other mRNAs. The protein encoded by this gene contains 3'-5' exoribonuclease activity and is a catalytic component of this complex. [provided by RefSeq, May 2016]

DIS3L links:

DIS3L-AS1 (HGNC:55369): (DIS3L antisense RNA 1)

DIS3L-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.859

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001143688.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIS3L	NM_001143688.3	MANE Select	c.67C>T	p.Arg23Cys	missense	Exon 1 of 17	NP_001137160.1	Q8TF46-1
DIS3L	NM_001323938.2		c.-263C>T		5_prime_UTR	Exon 1 of 17	NP_001310867.1	Q8TF46-2
DIS3L	NM_001323939.2		c.-460C>T		5_prime_UTR	Exon 1 of 18	NP_001310868.1	Q8TF46-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIS3L	ENST00000319212.9	TSL:5 MANE Select	c.67C>T	p.Arg23Cys	missense	Exon 1 of 17	ENSP00000321711.4	Q8TF46-1
DIS3L	ENST00000319194.9	TSL:1	c.-111+296C>T		intron	N/A	ENSP00000321583.5	Q8TF46-4
DIS3L	ENST00000904294.1		c.67C>T	p.Arg23Cys	missense	Exon 1 of 17	ENSP00000574353.1

Frequencies

GnomAD3 genomes

AF:

0.0000923

AC:

AN:

151630

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

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:

0.000206

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000268

AC:

AN:

74670

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000735

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000100

AC:

128

AN:

1277204

Hom.:

Cov.:

AF XY:

0.0000968

AC XY:

AN XY:

629932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25906

American (AMR)

AF:

0.00

AC:

AN:

24468

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21754

East Asian (EAS)

AF:

0.00

AC:

AN:

25860

South Asian (SAS)

AF:

0.00

AC:

AN:

69494

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31672

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3656

European-Non Finnish (NFE)

AF:

0.000109

AC:

111

AN:

1022646

Other (OTH)

AF:

0.000329

AC:

AN:

51748

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000923

AC:

AN:

151630

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74050

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41406

American (AMR)

AF:

0.00

AC:

AN:

15212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

67824

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000712

Hom.:

Bravo

AF:

0.0000718

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (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

0.35

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.70

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.86

MetaSVM

Benign

-0.48

MutationAssessor

Pathogenic

3.1

PhyloP100

2.4

PrimateAI

Pathogenic

0.93

PROVEAN

Pathogenic

-5.8

REVEL

Uncertain

0.56

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.64

MVP

0.59

MPC

0.81

ClinPred

0.87

GERP RS

2.7

PromoterAI

0.067

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

gMVP

0.66

Mutation Taster

=70/30

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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