PPP1R15B

protein-coding

protein phosphatase 1 regulatory subunit 15B, the group of Protein phosphatase 1 regulatory subunits

Gene summary

This gene encodes a protein phosphatase I-interacting protein that promotes the dephosphorylation of eukaryotic translation initiation factor 2A to regulate translation under conditions of cellular stress. The transcribed messenger RNA contains two upstream open reading frames (ORFs) that repress translation of the main protein coding ORF under normal conditions, while the protein coding ORF is expressed at high levels in response to stress. Continual translation of the mRNA under conditions of eukaryotic translation initiation factor 2A inactivation is thought to create a feedback loop for reactivation of the gene during recovery from stress. In addition, it has been shown that this protein plays a role in membrane traffic that is independent of translation and that it is required for exocytosis from erythroleukemia cells. Allelic variants of this gene are associated with microcephaly, short stature, and impaired glucose metabolism. [provided by RefSeq, Feb 2016]

MANE transcript

NM_032833.5

Inheritance

ClinVar variants

P:2U:165B:57

Top phenotype

Microcephaly, short stature, and impaired glucose metabolism 2

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr1:204,396,492-204,411,887

External References & Databases

Ensembl (ENSG00000158615)

Transcript & Mutation Effects

hg38 • Region Span ~15.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

primary microcephaly-mild intellectual disability-young-onset diabetes syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018320

Submitter: Orphanet

microcephaly, short stature, and impaired glucose metabolism 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014785

Submitter: Genomics England PanelApp

microcephaly, short stature, and impaired glucose metabolism 2MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014785

Submitter: PanelApp Australia

microcephaly, short stature, and impaired glucose metabolism 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014785

Submitter: G2P

microcephaly, short stature, and impaired glucose metabolism 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014785

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Microcephaly, short stature, and impaired glucose metabolism 2AR

Manifestation: Craniofacial; Endocrine; Musculoskeletal; Neurologic

Intervention: Endocrine

Rationale: Awareness of the risk of diabetes may allow prompt recognition and treatment

Refs: 26159176; 26307080

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PPP1R15B variants in ClinVar

5 Conditions Cataloged

not providedTotal: 152

Inborn genetic diseasesTotal: 97

PPP1R15B-related disorderTotal: 11

not specifiedTotal: 10

Microcephaly, short stature, and impaired glucose metabolism 2Total: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032833.5. 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			1 clinvar	41 clinvar	1 clinvar	43
missense		2 clinvar	157 clinvar	13 clinvar	2 clinvar	174
nonsense			4 clinvar			4
start loss			1 clinvar			1
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)						0
Total	0	2	165	54	3	224

Highest pathogenic variant AF is 0.0000034204593

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 8 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032833.5	RefSeq	NP_116222.4	2	MANE Select
ENST00000367188.5	Ensembl	ENSP00000356156.4	2	MANE Select
ENST00000689921.1	Ensembl	ENSP00000510434.1	2	Standard
ENST00000690849.1	Ensembl	ENSP00000509193.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of protein phosphorylation
ER overload response
positive regulation of phosphoprotein phosphatase activity
response to endoplasmic reticulum stress
response to hydrogen peroxide

Molecular Function

protein binding
protein phosphatase regulator activity

Cellular Component

protein phosphatase type 1 complex
cytoplasm
endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367188
Coding exons: 2
Length: 8405
Individuals with no LoFs: 125734
Homozygous LoFs: 0
Heterozygous LoFs: 14
Defined: 125748
p: 0.0000557

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.35	431	359	1.20	0.0000164	4637
Missense (PolyPhen)		114	105.06	1.0851		1446
Synonymous	-0.790	154	142	1.08	0.00000655	1441
Loss of Function	3.33	6	23.4	0.257	0.00000109	291

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000035	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Maintains low levels of EIF2S1 phosphorylation in unstressed cells by promoting its dephosphorylation by PP1. {ECO:0000269|PubMed:26159176, ECO:0000269|PubMed:26307080}.;
Disease: DISEASE: Microcephaly, short stature, and impaired glucose metabolism 2 (MSSGM2) [MIM:616817]: A disease characterized by microcephaly, mental retardation, short stature, and disturbed glucose metabolism. {ECO:0000269|PubMed:26159176, ECO:0000269|PubMed:26307080}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Defects in PPP1R15B has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea. {ECO:0000269|PubMed:28493397}.;

Recessive Scores

pRec: 0.0818

Intolerance Scores

LoFtool: 0.349
RVIS EVS: 0.73
RVIS percentile EVS: 86.3

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: N
Indispensability score: 0.235

Gene Damage Prediction

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