rs1553609835

Variant names:

• chr2-232130637-C-T
• rs1553609835
• NM_152383.5:c.620C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152383.5(DIS3L2):​c.620C>T​(p.Ala207Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. A207T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.111
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.054357767).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.620C>T	p.Ala207Val	missense_variant	Exon 7 of 21	ENST00000325385.12	NP_689596.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.620C>T	p.Ala207Val	missense_variant	Exon 7 of 21	5	NM_152383.5	ENSP00000315569.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Perlman syndrome Uncertain:1

Jul 09, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with valine at codon 207 of the DIS3L2 protein (p.Ala207Val). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with DIS3L2-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.8
DANN	Benign	0.89
DEOGEN2	Benign	0.0	.;T;.;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.60	T;T;.;.
M_CAP	Benign	0.0047	T
MetaRNN	Benign	0.054	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;N;N
PhyloP100		0.11
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.98	N;N;N;N
REVEL	Benign	0.011
Sift	Benign	0.23	T;T;D;T
Sift4G	Benign	0.28	T;T;T;T
Vest4		0.077
ClinPred		0.023	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.20
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs1553609835; hg19: chr2-232995347;