rs776359062

Variant names:

• chr2-232249299-G-A
• rs776359062
• NM_152383.5:c.1378G>A

Variant summary

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

The NM_152383.5(DIS3L2):​c.1378G>A​(p.Asp460Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: DIS3L2 NM_152383.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.29

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, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_152383.5	c.1378G>A	p.Asp460Asn	missense_variant	Exon 12 of 21	ENST00000325385.12	NP_689596.4
DIS3L2	NM_001257281.2	c.1378G>A	p.Asp460Asn	missense_variant	Exon 12 of 14		NP_001244210.1
DIS3L2	NR_046476.2	n.1524G>A		non_coding_transcript_exon_variant	Exon 12 of 21
DIS3L2	NR_046477.2	n.1500G>A		non_coding_transcript_exon_variant	Exon 11 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000325385.12	c.1378G>A	p.Asp460Asn	missense_variant	Exon 12 of 21	5	NM_152383.5	ENSP00000315569.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000801 AC: 2 AN: 249722 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135374

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000825 AC XY: 6 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Perlman syndrome Uncertain:1

Apr 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 460 of the DIS3L2 protein (p.Asp460Asn). This variant is present in population databases (rs776359062, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with DIS3L2-related conditions. ClinVar contains an entry for this variant (Variation ID: 410752). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DIS3L2 protein function with a negative predictive value of 80%. 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	0.25
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	.;T;T;T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;.;D
M_CAP	Uncertain	0.091	D
MetaRNN	Pathogenic	0.81	D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.9	M;M;M;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-4.1	D;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D
Polyphen		1.0	.;D;D;.
Vest4		0.90
MutPred		0.77		Gain of methylation at K461 (P = 0.0646);Gain of methylation at K461 (P = 0.0646);Gain of methylation at K461 (P = 0.0646);.;
MVP		0.30
MPC		0.81
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.71
gMVP		0.66

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: rs776359062; hg19: chr2-233114009; COSMIC: COSV99806499; COSMIC: COSV99806499;