UPF3B

protein-coding

UPF3B regulator of nonsense mediated mRNA decay, the group of DECID complex

Gene summary

This gene encodes a protein that is part of a post-splicing multiprotein complex involved in both mRNA nuclear export and mRNA surveillance. The encoded protein is one of two functional homologs to yeast Upf3p. mRNA surveillance detects exported mRNAs with truncated open reading frames and initiates nonsense-mediated mRNA decay (NMD). When translation ends upstream from the last exon-exon junction, this triggers NMD to degrade mRNAs containing premature stop codons. This protein binds to the mRNA and remains bound after nuclear export, acting as a nucleocytoplasmic shuttling protein. It forms with Y14 a complex that binds specifically 20 nt upstream of exon-exon junctions. This gene is located on the long arm of chromosome X. Two splice variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:

MRX62
UPF3BP1
UPF3BP2
UPF3BP3

MANE transcript

NM_080632.3

Inheritance

ClinVar variants

P:40U:194B:75

Top phenotype

Intellectual developmental disorder, X-linked, syndromic 14

gnomAD constraint

pLI —, LoF o/e 0.09

Max pathogenic AF

—

Genomic locus

chrX:119,834,022-119,852,998

External References & Databases

Ensembl (ENSG00000125351)

Transcript & Mutation Effects

hg38 • Region Span ~19.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

X-linked intellectual disability with marfanoid habitusSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010655

Submitter: Orphanet

non-syndromic X-linked intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

X-linked complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0100148

Submitter: ClinGen

*UPF3B* was first reported in relation to X-linked complex neurodevelopmental disorder in 2007 (Tarpey et al, PMID: 22957832). UPF3B is involved, along with UPF3A and UPF2, in the exon junction complex, mRNA nuclear export, and mRNA surveillance, initiating nonsense-mediated decay of mRNAs with truncated open reading frames. Observed phenotypes in affected males include, but are not limited to, facial dysmorphism, varying severity of intellectual disability, seizures, ADHD, childhood-onset schizophrenia, and other behavioral problems. Ten variants (nonsense, frameshift) that have been reported in 10 probands in 5 publications (PMIDs: 17704778, 19238151, 20479756, 22609145, 22957832) are included in this curation. Variants in this gene segregated with disease in 24 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. The mechanism of pathogenicity is reported to be hemizygous loss of function. This gene-disease relationship is also supported by *in vitro* functional assays and a *Upf3b*-null mouse model (PMIDs: 23821644, 26012578, 28948974). Variants in *UPF3B* are reported to affect neuronal development by impairing the nonsense-mediated decay mechanism. In summary, there is definitive evidence supporting the relationship between *UPF3B* and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on July 3, 2019 (SOP Version 6).

syndromic X-linked intellectual disability 14MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010398

Submitter: Ambry Genetics

syndromic X-linked intellectual disability 14STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010398

Submitter: PanelApp Australia

syndromic X-linked intellectual disability 14STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010398

Submitter: Labcorp Genetics (formerly Invitae)

syndromic X-linked intellectual disability 14DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010398

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked, syndromic 14XL

Manifestation: Craniofacial; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Nonsyndromic forms have been described in addition to the initial reports of individuals with syndromic mental retardation

Refs: 9805132; 17704778; 19377476; 22957832

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UPF3B variants in ClinVar

12 Conditions Cataloged

Syndromic X-linked intellectual disability 14Total: 234

not providedTotal: 83

Inborn genetic diseasesTotal: 54

not specifiedTotal: 12

UPF3B-related disorderTotal: 8

Neurodevelopmental disorderTotal: 2

Intellectual disabilityTotal: 2

CataractTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_080632.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			11 clinvar	44 clinvar	7 clinvar	62
missense	3 clinvar		148 clinvar	19 clinvar	5 clinvar	175
nonsense	4 clinvar	6 clinvar	8 clinvar			18
start loss	1 clinvar					1
frameshift	19 clinvar	4 clinvar	2 clinvar			25
splice donor/acceptor (+/-2bp)		3 clinvar	25 clinvar			28
Total	27	13	194	63	12	309

Highest pathogenic variant AF is 0.000010949285

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 28 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_080632.3	RefSeq	NP_542199.1	11	MANE Select
ENST00000276201.7	Ensembl	ENSP00000276201.3	11	MANE Select
NM_023010.4	RefSeq	NP_075386.1	10	Standard
ENST00000345865.6	Ensembl	ENSP00000245418.2	10	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

mRNA surveillance pathway - Homo sapiens (human)
RNA transport - Homo sapiens (human)
Gene expression (Transcription)
RNA Polymerase II Transcription
Metabolism of RNA

Biological Process

nuclear-transcribed mRNA catabolic process, nonsense-mediated decay
mRNA splicing, via spliceosome
RNA export from nucleus
mRNA export from nucleus
mRNA 3'-end processing

Molecular Function

RNA binding
mRNA binding
protein binding
structural constituent of nuclear pore

Cellular Component

nucleus
nucleoplasm
nucleolus
cytoplasm
microtubule organizing center

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000276201
Coding exons: 11
Length: 18977
Individuals with no LoFs: 125737
Homozygous LoFs: 2
Heterozygous LoFs: 0
Defined: 125739
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.84	112	182	0.615	0.0000139	3225
Missense (PolyPhen)		31	72.527	0.42743		1281
Synonymous	-0.450	63	58.6	1.07	0.00000414	808
Loss of Function	3.90	2	21.6	0.0928	0.00000188	368

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000024	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in nonsense-mediated decay (NMD) of mRNAs containing premature stop codons by associating with the nuclear exon junction complex (EJC) and serving as link between the EJC core and NMD machinery. Recruits UPF2 at the cytoplasmic side of the nuclear envelope and the subsequent formation of an UPF1-UPF2- UPF3 surveillance complex (including UPF1 bound to release factors at the stalled ribosome) is believed to activate NMD. In cooperation with UPF2 stimulates both ATPase and RNA helicase activities of UPF1. Binds spliced mRNA upstream of exon-exon junctions. In vitro, stimulates translation; the function is independent of association with UPF2 and components of the EJC core. {ECO:0000269|PubMed:11163187, ECO:0000269|PubMed:12718880, ECO:0000269|PubMed:16209946, ECO:0000269|PubMed:16601204, ECO:0000269|PubMed:18066079}.;

Recessive Scores

pRec: 0.120

Intolerance Scores

LoFtool: 0.440
RVIS EVS: 0.02
RVIS percentile EVS: 55.22

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.401

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium