GeneBe

CPSF3

protein-coding

cleavage and polyadenylation specific factor 3, the group of Cleavage and polyadenylation specific factor subunits|MBL fold containing DNA/RNA interacting subfamily|Endoribonucleases

Gene summary

This gene encodes a member of the metallo-beta-lactamase family. The encoded protein is a 73kDa subunit of the cleavage and polyadenylation specificity factor and functions as an endonuclease that recognizes the pre-mRNA 3'-cleavage site AAUAAA prior to polyadenylation. It also cleaves after the pre-mRNA sequence ACCCA during histone 3'-end pre-mRNA processing. [provided by RefSeq, Oct 2012]

MANE transcript

NM_016207.4

Inheritance

AR

ClinVar variants

P:2U:64B:12

Top phenotype

Neurodevelopmental disorder with microcephaly, hypotonia, and seizures

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr2:9,423,651-9,473,101

External References & Databases

Ensembl (ENSG00000119203)NCBI Gene (51692)OMIM (606029)HGNC:2326GenCCUniProt (Q9UKF6)AlphaFoldClinVar (CPSF3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~49.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizuresLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859250

Submitter: Ambry Genetics

neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizuresLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859250

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizuresMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0859250

Submitter: G2P

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with microcephaly, hypotonia, and seizuresAR

Manifestation: Craniofacial; 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

Refs: 35121750Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CPSF3 variants in ClinVar

6 Conditions Cataloged
not specifiedTotal: 49
not providedTotal: 10
Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizuresTotal: 5
Neurodevelopmental disorder with hypotonia, microcephaly, and seizuresTotal: 2
HP:0001252; HP:0001776; HP:0000252; HP:0001270; HP:0000592Total: 1
CPSF3-related conditionTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016207.4. 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.

EffectPLPVUSLBBSum
synonymous
3
clinvar
11
clinvar
 14
missense
1
clinvar
53
clinvar
1
clinvar
 55
nonsense
0
start loss
0
frameshift
0
splice donor/acceptor (+/-2bp)
1
clinvar
8
clinvar
 9
Total116412078
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_016207.4RefSeqNP_057291.118MANE Select
ENST00000238112.8EnsemblENSP00000238112.318MANE Select
NM_001321833.2RefSeqNP_001308762.117Standard
NM_001321834.2RefSeqNP_001308763.117Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
cpsf3Danio rerio

Structure: head

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • mRNA surveillance pathway - Homo sapiens (human)
  • mRNA Processing
  • Gene expression (Transcription)
  • polyadenylation of mrna
  • RNA Polymerase II Transcription

Biological Process

  • mRNA splicing, via spliceosome
  • termination of RNA polymerase II transcription
  • mRNA polyadenylation
  • mRNA cleavage
  • mRNA 3'-end processing by stem-loop binding and cleavage

Molecular Function

  • RNA binding
  • endoribonuclease activity
  • protein binding
  • 5'-3' exonuclease activity
  • metal ion binding

Cellular Component

  • nucleoplasm
  • mRNA cleavage and polyadenylation specificity factor complex

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000238112
Coding exons
18
Length
49534
Individuals with no LoFs
125673
Homozygous LoFs
0
Heterozygous LoFs
75
Defined
125748
p
0.000298
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense3.611783750.4750.00001904550
Missense (PolyPhen)451200.374991477
Synonymous0.7441211320.9180.000007501235
Loss of Function2.981736.40.4670.00000169474

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000250.00025rare
Latino/Admixed American0.000300.00029rare
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish0.0000480.000046rare
European (Non-Finnish)0.000330.00033rare
South Asian0.000670.00065rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Component of the cleavage and polyadenylation specificity factor (CPSF) complex that play a key role in pre-mRNA 3'-end formation, recognizing the AAUAAA signal sequence and interacting with poly(A) polymerase and other factors to bring about cleavage and poly(A) addition. Has endonuclease activity, and functions as mRNA 3'-end-processing endonuclease. Also involved in the histone 3'-end pre-mRNA processing. U7 snRNP- dependent protein that induces both the 3'-endoribonucleolytic cleavage of histone pre-mRNAs and acts as a 5' to 3' exonuclease for degrading the subsequent downstream cleavage product (DCP) of mature histone mRNAs. Cleavage occurs after the 5'-ACCCA-3' sequence in the histone pre-mRNA leaving a 3'hydroxyl group on the upstream fragment containing the stem loop (SL) and 5' phosphate on the downstream cleavage product (DCP) starting with CU nucleotides. The U7-dependent 5' to 3' exonuclease activity is processive and degrades the DCP RNA substrate even after complete removal of the U7-binding site. Binds to the downstream cleavage product (DCP) of histone pre-mRNAs and the cleaved DCP RNA substrate in a U7 snRNP dependent manner. {ECO:0000269|PubMed:14749727, ECO:0000269|PubMed:15037765, ECO:0000269|PubMed:17128255, ECO:0000269|PubMed:18688255}.;

Intolerance Scores

LoFtool
0.765
RVIS EVS
-0.56
RVIS percentile EVS
19.54

Essentials

Essential (CRISPR)
E
Essential (CRISPR2)
E
Essential (gene trap)
E
Indispensability pred.
E
Indispensability score
0.967

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.