PUM1

protein-coding

pumilio RNA binding family member 1, the group of Small nucleolar RNA protein coding host genes|Pumilio homology domain containing

Gene summary

This gene encodes a member of the PUF family, evolutionarily conserved RNA-binding proteins related to the Pumilio proteins of Drosophila and the fem-3 mRNA binding factor proteins of C. elegans. The encoded protein contains a sequence-specific RNA binding domain comprised of eight repeats and N- and C-terminal flanking regions, and serves as a translational regulator of specific mRNAs by binding to their 3' untranslated regions. The evolutionarily conserved function of the encoded protein in invertebrates and lower vertebrates suggests that the human protein may be involved in translational regulation of embryogenesis, and cell development and differentiation. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001020658.2

Inheritance

ClinVar variants

P:27U:252B:43

Top phenotype

Spinocerebellar ataxia 47; Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphism

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr1:30,931,506-31,065,991

External References & Databases

Ensembl (ENSG00000134644)

Transcript & Mutation Effects

hg38 • Region Span ~134.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spinocerebellar ataxia 47LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0033482

Submitter: Ambry Genetics

neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphismMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0958231

Submitter: Ambry Genetics

spinocerebellar ataxia 47MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0033482

Submitter: Illumina

neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphismSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0958231

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Spinocerebellar ataxia 47; Neurodevelopmental disorder with motor abnormalities, seizures, and facial dysmorphismAD

Manifestation: Craniofacial; Genitourinary; 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

Refs: 29474920; 30903679; 31859446; 35386260

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PUM1 variants in ClinVar

15 Conditions Cataloged

not providedTotal: 192

Inborn genetic diseasesTotal: 82

Spinocerebellar ataxia 47Total: 39

PUM1-related disorderTotal: 26

not specifiedTotal: 14

PUM1-associated developmental disability-ataxia-seizure syndromeTotal: 9

Intellectual disabilityTotal: 2

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001020658.2. 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			6 clinvar	24 clinvar	3 clinvar	33
missense		6 clinvar	233 clinvar	15 clinvar	1 clinvar	255
nonsense	7 clinvar	4 clinvar	5 clinvar			16
start loss						0
frameshift	3 clinvar	5 clinvar				8
splice donor/acceptor (+/-2bp)		2 clinvar	8 clinvar			10
Total	10	17	252	39	4	322

Highest pathogenic variant AF is 0.0000020977789

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 435 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001020658.2	RefSeq	NP_001018494.1	21	MANE Select
ENST00000426105.7	Ensembl	ENSP00000391723.2	21	MANE Select
NM_014676.3	RefSeq	NP_055491.1	21	Standard
ENST00000257075.10	Ensembl	ENSP00000257075.5	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Golgi Associated Vesicle Biogenesis
Clathrin derived vesicle budding
trans-Golgi Network Vesicle Budding
Vesicle-mediated transport
Membrane Trafficking

Biological Process

spermatogenesis
adult locomotory behavior
posttranscriptional regulation of gene expression
posttranscriptional gene silencing
production of miRNAs involved in gene silencing by miRNA

Molecular Function

RNA binding
mRNA 3'-UTR binding
protein binding
miRNA binding

Cellular Component

P-body
nucleus
nucleoplasm
cytosol
cytoplasmic stress granule

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000426105
Coding exons: 21
Length: 134486
Individuals with no LoFs: 125743
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125748
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.42	361	687	0.525	0.0000389	7728
Missense (PolyPhen)		69	212.92	0.32406		2412
Synonymous	0.424	257	266	0.967	0.0000164	2401
Loss of Function	6.82	3	60.0	0.0500	0.00000325	645

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	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Sequence-specific RNA-binding protein that acts as a post-transcriptional repressor by binding the 3'-UTR of mRNA targets. Binds to an RNA consensus sequence, the Pumilio Response Element (PRE), 5'-UGUANAUA-3', that is related to the Nanos Response Element (NRE) (PubMed:21572425, PubMed:18328718, PubMed:21653694, PubMed:21397187). Mediates post-transcriptional repression of transcripts via different mechanisms: acts via direct recruitment of the CCR4-POP2-NOT deadenylase leading to translational inhibition and mRNA degradation (PubMed:22955276). Also mediates deadenylation-independent repression by promoting accessibility of miRNAs (PubMed:18776931, PubMed:20818387, PubMed:20860814, PubMed:22345517). Following growth factor stimulation, phosphorylated and binds to the 3'-UTR of CDKN1B/p27 mRNA, inducing a local conformational change that exposes miRNA- binding sites, promoting association of miR-221 and miR-222, efficient suppression of CDKN1B/p27 expression, and rapid entry to the cell cycle (PubMed:20818387). Acts as a post-transcriptional repressor of E2F3 mRNAs by binding to its 3'-UTR and facilitating miRNA regulation (PubMed:22345517, PubMed:29474920). Represses a program of genes necessary to maintain genomic stability such as key mitotic, DNA repair and DNA replication factors. Its ability to repress those target mRNAs is regulated by the lncRNA NORAD (non-coding RNA activated by DNA damage) which, due to its high abundance and multitude of PUMILIO binding sites, is able to sequester a significant fraction of PUM1 and PUM2 in the cytoplasm (PubMed:26724866). Involved in neuronal functions by regulating ATXN1 mRNA levels: acts by binding to the 3'-UTR of ATXN1 transcripts, leading to their down-regulation independently of the miRNA machinery (PubMed:25768905, PubMed:29474920). Plays a role in cytoplasmic sensing of viral infection (PubMed:25340845). In testis, acts as a post-transcriptional regulator of spermatogenesis by binding to the 3'-UTR of mRNAs coding for regulators of p53/TP53. Involved in embryonic stem cell renewal by facilitating the exit from the ground state: acts by targeting mRNAs coding for naive pluripotency transcription factors and accelerates their down-regulation at the onset of differentiation (By similarity). Binds specifically to miRNA MIR199A precursor, with PUM2, regulates miRNA MIR199A expression at a postranscriptional level (PubMed:28431233). {ECO:0000250|UniProtKB:Q80U78, ECO:0000269|PubMed:18328718, ECO:0000269|PubMed:18776931, ECO:0000269|PubMed:20818387, ECO:0000269|PubMed:20860814, ECO:0000269|PubMed:21397187, ECO:0000269|PubMed:21572425, ECO:0000269|PubMed:21653694, ECO:0000269|PubMed:22345517, ECO:0000269|PubMed:22955276, ECO:0000269|PubMed:25340845, ECO:0000269|PubMed:25768905, ECO:0000269|PubMed:26724866, ECO:0000269|PubMed:28431233, ECO:0000269|PubMed:29474920}.;
Disease: DISEASE: Spinocerebellar ataxia 47 (SCA47) [MIM:617931]: A form of spinocerebellar ataxia, a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA47 is an autosomal dominant disease with a highly variable phenotype and incomplete penetrance. Clinical features include developmental disability, ataxia, and seizures. {ECO:0000269|PubMed:29474920}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.163

Intolerance Scores

LoFtool: 0.229
RVIS EVS: -1.02
RVIS percentile EVS: 8.1

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.915

Gene Damage Prediction

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