rs1060503039

Variant names:

• chr2-232333894-T-C
• rs1060503039
• NM_152383.5:c.2065T>C

Your query was ambiguous. Multiple possible variants found:

• chr2-232333894-T-C
• chr2-232333894-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.05

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.833

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.2065T>C	p.Tyr689His	missense_variant	Exon 17 of 21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2	c.1582-9451T>C		intron_variant	Intron 13 of 13		NP_001244210.1
DIS3L2	NR_046476.2	n.2138T>C		non_coding_transcript_exon_variant	Exon 17 of 21
DIS3L2	NR_046477.2	n.2117T>C		non_coding_transcript_exon_variant	Exon 16 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.2065T>C	p.Tyr689His	missense_variant	Exon 17 of 21	5	NM_152383.5	ENSP00000315569.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T;T;T
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.96	D;.;D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Pathogenic	3.2	M;M;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.97
MutPred		0.78		Gain of disorder (P = 0.0626);Gain of disorder (P = 0.0626);.;
MVP		0.068
MPC		0.94
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.91
gMVP		0.91

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: rs1060503039; hg19: chr2-233198604;