rs1553612391

Positions:

• chr2-232163623-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_152383.5(DIS3L2):​c.1115G>C​(p.Arg372Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R372R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIS3L2	NM_152383.5	c.1115G>C	p.Arg372Thr	missense_variant	9/21	ENST00000325385.12
DIS3L2	NM_001257281.2	c.1115G>C	p.Arg372Thr	missense_variant	9/14
DIS3L2	NR_046476.2	n.1261G>C		non_coding_transcript_exon_variant	9/21
DIS3L2	NR_046477.2	n.1237G>C		non_coding_transcript_exon_variant	8/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L2	ENST00000325385.12	c.1115G>C	p.Arg372Thr	missense_variant	9/21	5	NM_152383.5	P1

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 12, 2018

This variant has not been reported in the literature in individuals with DIS3L2-related disease. ClinVar contains an entry for this variant (Variation ID: 463047). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with threonine at codon 372 of the DIS3L2 protein (p.Arg372Thr). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and threonine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Benign	0.19	.;T;T;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D;D;.;D
M_CAP	Benign	0.042	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.2	M;M;M;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Benign	0.19
Sift	Benign	0.048	D;D;D;T
Sift4G	Uncertain	0.010	D;D;D;T
Polyphen		0.65	.;P;P;.
Vest4		0.47
MutPred		0.75		Gain of phosphorylation at R372 (P = 0.0311);Gain of phosphorylation at R372 (P = 0.0311);Gain of phosphorylation at R372 (P = 0.0311);.;
MVP		0.043
MPC		0.97
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.39
gMVP		0.80

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

LitVar

Other links and lift over

dbSNP: rs1553612391; hg19: chr2-233028333;