rs201733073

chr2-232087530-A-G

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

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. 14/21 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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:3
• Conservation: PhyloP100: 0.893

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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 id is 241980.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2, Benign=1}.
• 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 male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIS3L2	NM_152383.5	c.410A>G	p.Tyr137Cys	missense_variant	6/21	ENST00000325385.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L2	ENST00000325385.12	c.410A>G	p.Tyr137Cys	missense_variant	6/21	5	NM_152383.5	P1

Frequencies

GnomAD3 genomes AF: 0.000697 AC: 106 AN: 152006 Hom.: 0 Cov.: 31

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

GnomAD3 exomes AF: 0.000714 AC: 178 AN: 249458 Hom.: 0 AF XY: 0.000754 AC XY: 102 AN XY: 135332

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 SAS 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.: 1 Cov.: 31 AF XY: 0.000877 AC XY: 638 AN XY: 727204

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000262

Gnomad4 NFE exome AF: 0.00111

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000697 AC: 106 AN: 152124 Hom.: 0 Cov.: 31 AF XY: 0.000753 AC XY: 56 AN XY: 74380

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000945

Gnomad4 NFE AF: 0.00132

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.000888

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00157 AC: 13

ExAC AF: 0.000778 AC: 94

EpiCase AF: 0.00147

EpiControl AF: 0.00142

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Perlman syndrome Uncertain:2 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Dec 25, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 05, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 31, 2022	Observed in the heterozygous state in individuals with Wilms tumor, microophthalmia, and agenesis of the corpus callosum (Leung GKC et al., 2018; Wegert J et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25670083, 30359267, 30344923) -

DIS3L2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 15, 2022

The DIS3L2 c.410A>G variant is predicted to result in the amino acid substitution p.Tyr137Cys. This variant was observed in an individual with blastemal type Wilms tumor, although no further studies were performed to determine its pathogenicity (Wegert et al. 2015. PubMed ID: 25670083). This variant was also reported in the compound heterozygous state with a second missense variant in an individual with microophthalmia and agenesis of corpus callosum (Leung et al 2018. PubMed ID: 30359267). This variant is reported in 0.13% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-232952240-A-G) and has conflicting interpretations of benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/241980/). Although we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	15
Dann	Uncertain	0.99
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.76	T;T;.;T;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.020	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	M;M;M;.;M
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.84	N;N;N;N;N
REVEL	Benign	0.048
Sift	Benign	0.15	T;T;T;T;T
Sift4G	Benign	0.17	T;T;T;T;T
Polyphen		0.90, 0.96	.;P;D;.;P
Vest4		0.13
MVP		0.068
MPC		0.28
ClinPred		0.013	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.31

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

LitVar

Other links and lift over

dbSNP: rs201733073; hg19: chr2-232952240;