rs555184370

Positions:

• chr2-232329813-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_152383.5(DIS3L2):​c.1740G>T​(p.Lys580Asn) variant causes a missense, splice region change. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. K580R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000049 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIS3L2 NM_152383.5 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.85

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.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIS3L2	NM_152383.5	c.1740G>T	p.Lys580Asn	missense_variant, splice_region_variant	15/21	ENST00000325385.12
DIS3L2	NM_001257281.2	c.1582-13532G>T		intron_variant
DIS3L2	NR_046476.2	n.1886-73G>T		intron_variant, non_coding_transcript_variant
DIS3L2	NR_046477.2	n.1862-70G>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIS3L2	ENST00000325385.12	c.1740G>T	p.Lys580Asn	missense_variant, splice_region_variant	15/21	5	NM_152383.5	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 1 AN: 139548 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000256

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000492 AC: 2 AN: 406176 Hom.: 0 Cov.: 10 AF XY: 0.00000474 AC XY: 1 AN XY: 210992

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000325

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000716 AC: 1 AN: 139696 Hom.: 0 Cov.: 31 AF XY: 0.0000148 AC XY: 1 AN XY: 67688

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000256

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000250 AC: 3

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

Sep 10, 2023

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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 463073). This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 580 of the DIS3L2 protein (p.Lys580Asn). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;.;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.14	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.4	N;N;D
REVEL	Benign	0.15
Sift	Uncertain	0.011	D;D;T
Sift4G	Uncertain	0.041	D;D;T
Polyphen		0.036	B;B;.
Vest4		0.64
MutPred		0.69		Loss of ubiquitination at K580 (P = 0.021);Loss of ubiquitination at K580 (P = 0.021);.;
MVP		0.15
MPC		0.40
ClinPred		0.61	D
GERP RS		5.3
Varity_R		0.36
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.070		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: rs555184370; hg19: chr2-233194523;