PURA

protein-coding

purine rich element binding protein A

Gene summary

This gene product is a sequence-specific, single-stranded DNA-binding protein. It binds preferentially to the single strand of the purine-rich element termed PUR, which is present at origins of replication and in gene flanking regions in a variety of eukaryotes from yeasts through humans. Thus, it is implicated in the control of both DNA replication and transcription. Deletion of this gene has been associated with myelodysplastic syndrome and acute myelogenous leukemia. [provided by RefSeq, Jul 2008]

MANE transcript

NM_005859.5

Inheritance

ClinVar variants

P:229U:169B:185

Top phenotype

Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficulties

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr5:140,107,777-140,125,619

External References & Databases

Ensembl (ENSG00000185129)

Transcript & Mutation Effects

hg38 • Region Span ~17.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutationSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014512

Submitter: Orphanet

complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0100038

Submitter: ClinGen

Pathogenic variants in the PURA gene were initially reported in relation to autosomal dominant PURA syndrome, a complex neurodevelopmental disorder, in 2014 (Lalani et al. PMID: 25439098). At least 50 unique variants variants (e.g. missense, in-frame indel, nonsense, frameshift, large deletions) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. More evidence is available in the literature, but the maximum score for genetic evidence and experimental evidence (12 pts.) has been reached. In summary, PURA is definitively associated with an autosomal dominant complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutationDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014512

Submitter: G2P

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutationSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014512

Submitter: Labcorp Genetics (formerly Invitae)

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutationSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014512

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with neonatal respiratory insufficiency, hypotonia, and feeding difficultiesAD

Manifestation: Craniofacial; Endocrine; 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: 25342064; 25439098; 25533962

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PURA variants in ClinVar

21 Conditions Cataloged

PURA-related severe neonatal hypotonia-seizures-encephalopathy syndromeTotal: 470

not providedTotal: 190

Inborn genetic diseasesTotal: 69

not specifiedTotal: 39

PURA-related disorderTotal: 38

Intellectual disabilityTotal: 16

Global developmental delayTotal: 11

Delayed speech and language developmentTotal: 11

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005859.5. 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			31 clinvar	142 clinvar	9 clinvar	182
missense	15 clinvar	52 clinvar	136 clinvar	25 clinvar	9 clinvar	237
nonsense	29 clinvar	12 clinvar	1 clinvar			42
start loss	4 clinvar	2 clinvar				6
frameshift	79 clinvar	36 clinvar	1 clinvar			116
splice donor/acceptor (+/-2bp)						0
Total	127	102	169	167	18	583

Highest pathogenic variant AF is 0.000018034085

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 6 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005859.5	RefSeq	NP_005850.1	1	MANE Select
ENST00000331327.5	Ensembl	ENSP00000332706.3	1	MANE Select
ENST00000502351.1	Ensembl	ENSP00000498760.1	1	Standard
ENST00000505703.2	Ensembl	ENSP00000498560.1	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

miR-targeted genes in epithelium - TarBase
miR-targeted genes in lymphocytes - TarBase
Exercise-induced Circadian Regulation

Biological Process

negative regulation of transcription by RNA polymerase II
DNA unwinding involved in DNA replication
DNA replication initiation
nervous system development
positive regulation of cell population proliferation

Molecular Function

translation repressor activity, mRNA regulatory element binding
RNA polymerase II regulatory region sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA-binding transcription repressor activity, RNA polymerase II-specific
double-stranded DNA binding

Cellular Component

nuclear chromosome, telomeric region
nucleus
DNA replication factor A complex
dendrite cytoplasm
neuronal cell body

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000331327
Coding exons: 1
Length: 8960
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.37	39	158	0.246	0.00000741	2080
Missense (PolyPhen)		8	94.151	0.08497		1065
Synonymous	-3.51	110	72.1	1.53	0.00000344	680
Loss of Function	2.77	0	8.93	0.00	3.82e-7	104

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	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This is a probable transcription activator that specifically binds the purine-rich single strand of the PUR element located upstream of the MYC gene. May play a role in the initiation of DNA replication and in recombination.;
Disease: DISEASE: Mental retardation, autosomal dominant 31 (MRD31) [MIM:616158]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD31 patients manifest neonatal hypotonia, encephalopathy with or without epilepsy, and severe developmental delay. {ECO:0000269|PubMed:25342064, ECO:0000269|PubMed:25439098}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.200

Intolerance Scores

RVIS EVS: -0.12
RVIS percentile EVS: 44.54

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.925

Gene Damage Prediction

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