Genetic Variant DIS3L2:p.Phe575Leu (chr2-232343486-T-C) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_001257281.2(DIS3L2):c.1723T>C(p.Phe575Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000392 in 1,556,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 10/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

DIS3L2
NM_001257281.2 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 4.33

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08094886).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000197 (30/152060) while in subpopulation AFR AF= 0.000677 (28/41384). AF 95% confidence interval is 0.00048. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIS3L2	NM_001257281.2 link	c.1723T>C	p.Phe575Leu	missense_variant	Exon 14 of 14		NP_001244210.1	Q8IYB7-3
NRBF2P6		n.232343486T>C		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIS3L2	ENST00000273009.10 link	c.1723T>C	p.Phe575Leu	missense_variant	Exon 14 of 14	2		ENSP00000273009.6		Q8IYB7-3
NRBF2P6	ENST00000513620.1 link	n.371T>C		non_coding_transcript_exon_variant	Exon 1 of 1	6

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000677

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000615

AC:

AN:

162702

Hom.:

AF XY:

0.0000463

AC XY:

AN XY:

86398

show subpopulations

Gnomad AFR exome

AF:

0.000750

Gnomad AMR exome

AF:

0.000119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000431

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000221

AC:

AN:

1404020

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

692994

show subpopulations

Gnomad4 AFR exome

AF:

0.000695

Gnomad4 AMR exome

AF:

0.0000831

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.24e-7

Gnomad4 OTH exome

AF:

0.0000857

GnomAD4 genome

AF:

0.000197

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.000677

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000479

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000355

ExAC

AF:

0.0000444

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

DIS3L2-related disorder

Uncertain:1

Feb 17, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The DIS3L2 c.1723T>C variant is predicted to result in the amino acid substitution p.Phe575Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.066% of alleles in individuals of African descent in gnomAD, indicating it is rare. This variant is not present in ClinVar. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.67

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.80

M_CAP

Benign

0.00062

MetaRNN

Benign

0.081

MetaSVM

Benign

-0.99

PROVEAN

Benign

0.51

REVEL

Benign

0.057

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.38

MutPred

0.56

Loss of sheet (P = 0.0037);

MVP

0.043

ClinPred

0.10

GERP RS

0.12

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