Genetic Variant DIS3L2:p.Val709Phe (chr2-232333954-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_152383.5(DIS3L2):c.2125G>T(p.Val709Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V709I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DIS3L2
NM_152383.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.269

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Perlman syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P

DIS3L2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.886

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152383.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DIS3L2	NM_152383.5	MANE Select	c.2125G>T	p.Val709Phe	missense	Exon 17 of 21	NP_689596.4
DIS3L2	NR_046476.2		n.2198G>T		non_coding_transcript_exon	Exon 17 of 21
DIS3L2	NR_046477.2		n.2177G>T		non_coding_transcript_exon	Exon 16 of 19

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DIS3L2	ENST00000325385.12	TSL:5 MANE Select	c.2125G>T	p.Val709Phe	missense	Exon 17 of 21	ENSP00000315569.7
DIS3L2	ENST00000390005.9	TSL:1	n.*192G>T		non_coding_transcript_exon	Exon 17 of 21	ENSP00000374655.5
DIS3L2	ENST00000445090.5	TSL:1	n.*1281G>T		non_coding_transcript_exon	Exon 16 of 19	ENSP00000388999.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460356

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726516

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26104

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52238

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111786

Other (OTH)

AF:

0.00

AC:

AN:

60360

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Uncertain

0.37

Eigen_PC

Benign

0.19

FATHMM_MKL

Benign

0.66

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-0.70

MutationAssessor

Pathogenic

3.6

PhyloP100

0.27

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.26

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0060

Polyphen

0.98

Vest4

0.88

MutPred

0.82

Loss of helix (P = 0.1299)

MVP

0.51

MPC

0.89

ClinPred

0.99

GERP RS

1.4

PromoterAI

0.079

Neutral

(source)

Varity_R

0.65

gMVP

0.90

Mutation Taster

=57/43

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over