DIS3L2

Chr 2AR

DIS3 like 3'-5' exoribonuclease 2

Also known as: FAM6A, PRLMNS, hDIS3L2

NCBI Gene: 129563 ENSG00000144535 UniProt: Q8IYB7 OMIM: 614184

DIS3L2 encodes a 3'-5'-exoribonuclease that degrades polyuridylated RNAs, including mRNAs and miRNAs, and is essential for proper mitosis and cell proliferation regulation. Biallelic mutations cause Perlman syndrome, an autosomal recessive overgrowth disorder with neonatal onset. This gene is highly constrained against loss-of-function variants in the population.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Perlman syndromeMIM #267000

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Perlman syndrome · AR · ClinGen 2019

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.33

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — DIS3L2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.33LOEUF

pLI 0.944

Z-score 5.06

OE 0.18 (0.10–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

0.94Z-score

OE missense 0.89 (0.82–0.95)

477 obs / 538.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.18 (0.10–0.33)

0≤0.351.4

Missense OE?0.89 (0.82–0.95)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 8 / 44.4Missense obs/exp: 477 / 538.7Syn Z: -0.17

Background carrier burden — how many people carry a rare variant somewhere in DIS3L2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 43

1,407 rare PASS variants

Rare truncating (LoF)

1 in 640

180 rare PASS variants

Rare synonymous (reference)

1 in 72

584 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DIS3L2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 51	1 in 730
South Asian	~43k	1 in 32	1 in 430
Remaining (unassigned)	~30k	1 in 36	1 in 590
European (Finnish)	~27k	1 in 170	1 in 1,300
Admixed American	~22k	1 in 36	1 in 730
African / African American	~21k	1 in 32	1 in 610
East Asian	~20k	1 in 32	1 in 530
Ashkenazi Jewish	~13k	1 in 85	1 in 430
Middle Eastern	~2,884	1 in 39	1 in 360

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 19 of 20 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: all 20.? see exons ↓