CPSF3

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

Basic information

Region (hg38): 2:9423651-9473101

Links

ENSG00000119203 ∙ NCBI:51692 ∙ OMIM:606029 ∙ HGNC:2326 ∙ Uniprot:Q9UKF6 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures (Limited), mode of inheritance: AR
• neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures (Limited), mode of inheritance: AR
• neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Neurodevelopmental disorder with microcephaly, hypotonia, and seizures	AR	General	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	Craniofacial; Neurologic	35121750

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the CPSF3 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the CPSF3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				2		2
missense			24	1		25
nonsense						0
start loss						0
frameshift						0
inframe indel						0
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding						0
Total	0	0	24	3	0

Variants in CPSF3

This is a list of pathogenic ClinVar variants found in the CPSF3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
2-9423789-G-T		not specified	Uncertain significance (Mar 15, 2024)
2-9428800-T-C		Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures	Uncertain significance (Mar 29, 2024)
2-9432588-T-C		not specified	Uncertain significance (Mar 25, 2024)
2-9432669-T-C		not specified	Uncertain significance (Jan 17, 2024)
2-9433955-A-G		not specified	Uncertain significance (Jan 29, 2025)
2-9436245-G-A		not specified	Uncertain significance (Aug 19, 2024)
2-9436254-G-A		Neurodevelopmental disorder with microcephaly, hypotonia, nystagmus, and seizures	Uncertain significance (Apr 28, 2023)
2-9441883-T-C			Likely benign (Feb 01, 2025)
2-9441918-C-T		not specified	Uncertain significance (Jun 29, 2023)
2-9441942-T-C		Neurodevelopmental disorder with hypotonia, microcephaly, and seizures • not specified	Uncertain significance (Sep 11, 2024)
2-9443518-A-G		not specified	Uncertain significance (Mar 12, 2024)
2-9443530-C-T		not specified	Uncertain significance (Feb 12, 2025)
2-9443579-C-T		not specified	Uncertain significance (Apr 07, 2022)
2-9443581-G-A		not specified	Uncertain significance (Sep 09, 2024)
2-9443619-G-C			Uncertain significance (Nov 30, 2021)
2-9448247-T-C		not specified	Uncertain significance (May 03, 2023)
2-9452920-G-A		Neurodevelopmental disorder with hypotonia, microcephaly, and seizures	Pathogenic (Jun 14, 2022)
2-9452935-A-G			Likely benign (Dec 01, 2022)
2-9452955-C-T		not specified	Uncertain significance (Mar 15, 2024)
2-9452956-G-A		not specified	Uncertain significance (Sep 14, 2022)
2-9452963-A-G			Likely benign (Mar 01, 2025)
2-9455693-G-A			Likely benign (Mar 01, 2022)
2-9455701-C-T		not specified	Uncertain significance (Sep 04, 2024)
2-9455713-C-G		not specified	Uncertain significance (Jul 09, 2024)
2-9456993-C-T		not specified	Uncertain significance (Nov 12, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
CPSF3	protein_coding	protein_coding	ENST00000238112	18	49534

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
3.03e-7	0.999	125673	0	75	125748	0.000298

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.61	178	375	0.475	0.0000190	4550
Missense in Polyphen		45	120	0.37499		1477
Synonymous	0.744	121	132	0.918	0.00000750	1235
Loss of Function	2.98	17	36.4	0.467	0.00000169	474

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000546	0.000543
Ashkenazi Jewish	0.00	0.00
East Asian	0.000112	0.000109
Finnish	0.0000476	0.0000462
European (Non-Finnish)	0.000330	0.000325
Middle Eastern	0.000112	0.000109
South Asian	0.000665	0.000653
Other	0.000164	0.000163

dbNSFP

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}.
• Pathway: mRNA surveillance pathway - Homo sapiens (human);mRNA Processing;Gene expression (Transcription);polyadenylation of mrna;RNA Polymerase II Transcription;Metabolism of RNA;Processing of Intronless Pre-mRNAs;Processing of Capped Intronless Pre-mRNA;Cleavage of Growing Transcript in the Termination Region ;RNA Polymerase II Transcription Termination;mRNA Splicing - Major Pathway;Transport of Mature mRNA Derived from an Intronless Transcript;Transport of Mature mRNAs Derived from Intronless Transcripts;mRNA Splicing;mRNA 3,-end processing;Transport of Mature Transcript to Cytoplasm;Processing of Capped Intron-Containing Pre-mRNA (Consensus)

Intolerance Scores

• loftool: 0.765
• rvis_EVS: -0.56
• rvis_percentile_EVS: 19.54

Haploinsufficiency Scores

• pHI: 0.167
• hipred: Y
• hipred_score: 0.706
• ghis: 0.705

Essentials

• essential_gene_CRISPR: E
• essential_gene_CRISPR2: E
• essential_gene_gene_trap: E
• gene_indispensability_pred: E
• gene_indispensability_score: 0.967

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Cpsf3
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Zebrafish Information Network

• Gene name: cpsf3
• Affected structure: head
• Phenotype tag: abnormal
• Phenotype quality: decreased size

Gene ontology

• 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;mRNA export from nucleus;mRNA 3'-end processing;RNA phosphodiester bond hydrolysis, endonucleolytic
• Cellular component: nucleoplasm;mRNA cleavage and polyadenylation specificity factor complex
• Molecular function: RNA binding;endoribonuclease activity;protein binding;5'-3' exonuclease activity;metal ion binding