Genetic Variant DIS3L2:c.*3A>C (chr2-232343578-A-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001257281.2(DIS3L2):c.*3A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00536 in 1,574,986 control chromosomes in the GnomAD database, including 131 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0085 ( 24 hom., cov: 33)

Exomes 𝑓: 0.0050 ( 107 hom. )

Consequence

DIS3L2
NM_001257281.2 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.00800

Variant links:

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 links:

NRBF2P6 (HGNC:54797): (NRBF2 pseudogene 6)

NRBF2P6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 2-232343578-A-C is Benign according to our data. Variant chr2-232343578-A-C is described in ClinVar as [Benign]. Clinvar id is 1236634.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_001257281.2 link	c.*3A>C		3_prime_UTR_variant	Exon 14 of 14		NP_001244210.1	Q8IYB7-3
NRBF2P6		n.232343578A>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000273009.10 link	c.*3A>C		3_prime_UTR_variant	Exon 14 of 14	2		ENSP00000273009.6		Q8IYB7-3
NRBF2P6	ENST00000513620.1 link	n.463A>C		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.00855

AC:

1301

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00150

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0491

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.0160

Gnomad SAS

AF:

0.0172

Gnomad FIN

AF:

0.0140

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00225

Gnomad OTH

AF:

0.00765

GnomAD3 exomes

AF:

0.0140

AC:

2728

AN:

195196

Hom.:

AF XY:

0.0130

AC XY:

1368

AN XY:

104884

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.0577

Gnomad ASJ exome

AF:

0.00130

Gnomad EAS exome

AF:

0.0165

Gnomad SAS exome

AF:

0.0161

Gnomad FIN exome

AF:

0.0118

Gnomad NFE exome

AF:

0.00157

Gnomad OTH exome

AF:

0.0107

GnomAD4 exome

AF:

0.00502

AC:

7144

AN:

1422654

Hom.:

107

Cov.:

AF XY:

0.00528

AC XY:

3718

AN XY:

703960

show subpopulations

Gnomad4 AFR exome

AF:

0.000780

Gnomad4 AMR exome

AF:

0.0543

Gnomad4 ASJ exome

AF:

0.00132

Gnomad4 EAS exome

AF:

0.0124

Gnomad4 SAS exome

AF:

0.0172

Gnomad4 FIN exome

AF:

0.0126

Gnomad4 NFE exome

AF:

0.00194

Gnomad4 OTH exome

AF:

0.00524

GnomAD4 genome

AF:

0.00854

AC:

1301

AN:

152332

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

809

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00149

Gnomad4 AMR

AF:

0.0491

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.0158

Gnomad4 SAS

AF:

0.0174

Gnomad4 FIN

AF:

0.0140

Gnomad4 NFE

AF:

0.00225

Gnomad4 OTH

AF:

0.00757

Alfa

AF:

0.00290

Hom.:

Bravo

AF:

0.00996

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 28, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

DIS3L2-related disorder

Benign:1

Jun 19, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

3.5

DANN

Benign

0.43

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over