Genetic Variant DIS3L2:p.Tyr689His (chr2-232333894-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_152383.5(DIS3L2):c.2065T>C(p.Tyr689His) variant causes a missense change. 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. Y689D) has been classified as Uncertain significance.

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: 6.05

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.833

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
DIS3L2	NM_152383.5	MANE Select	c.2065T>C	p.Tyr689His	missense	Exon 17 of 21	NP_689596.4
DIS3L2	NR_046476.2		n.2138T>C		non_coding_transcript_exon	Exon 17 of 21
DIS3L2	NR_046477.2		n.2117T>C		non_coding_transcript_exon	Exon 16 of 19

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.2065T>C	p.Tyr689His	missense	Exon 17 of 21	ENSP00000315569.7
DIS3L2	ENST00000390005.9	TSL:1	n.*132T>C		non_coding_transcript_exon	Exon 17 of 21	ENSP00000374655.5
DIS3L2	ENST00000445090.5	TSL:1	n.*1221T>C		non_coding_transcript_exon	Exon 16 of 19	ENSP00000388999.1

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

Oct 06, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tyrosine with histidine at codon 689 of the DIS3L2 protein (p.Tyr689His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a DIS3L2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Pathogenic

0.77

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

0.21

MutationAssessor

Pathogenic

3.2

PhyloP100

6.0

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.5

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.78

Gain of disorder (P = 0.0626)

MVP

0.068

MPC

0.94

ClinPred

1.0

GERP RS

4.3

PromoterAI

-0.029

Neutral

(source)

Varity_R

0.91

gMVP

0.91

Mutation Taster

=42/58

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over