IMPA1

protein-coding

inositol monophosphatase 1, the group of Phosphoinositide phosphatases

Gene summary

This gene encodes an enzyme that dephosphorylates myo-inositol monophosphate to generate free myo-inositol, a precursor of phosphatidylinositol, and is therefore an important modulator of intracellular signal transduction via the production of the second messengers myoinositol 1,4,5-trisphosphate and diacylglycerol. This enzyme can also use myo-inositol-1,3-diphosphate, myo-inositol-1,4-diphosphate, scyllo-inositol-phosphate, glucose-1-phosphate, glucose-6-phosphate, fructose-1-phosphate, beta-glycerophosphate, and 2'-AMP as substrates. This enzyme shows magnesium-dependent phosphatase activity and is inhibited by therapeutic concentrations of lithium. Inhibition of inositol monophosphate hydroylosis and subsequent depletion of inositol for phosphatidylinositol synthesis may explain the anti-manic and anti-depressive effects of lithium administered to treat bipolar disorder. Alternative splicing results in multiple transcript variants encoding distinct isoforms. A pseudogene of this gene is also present on chromosome 8q21.13. [provided by RefSeq, Dec 2014]

Previous symbols:

IMPA

MANE transcript

NM_005536.4

Inheritance

ClinVar variants

P:2U:35B:11

Top phenotype

Mental retardation, autosomal recessive 59

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr8:81,656,914-81,686,331

External References & Databases

Ensembl (ENSG00000133731)

Transcript & Mutation Effects

hg38 • Region Span ~29.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 59LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0015020

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal recessive 59MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0015020

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal recessive 59LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0015020

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Mental retardation, autosomal recessive 59AR

Manifestation: 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: 26416544

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IMPA1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 41

not providedTotal: 8

Intellectual disability, autosomal recessive 59Total: 5

IMPA1-related disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005536.4. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				7 clinvar		7
missense			33 clinvar	3 clinvar	1 clinvar	37
nonsense		1 clinvar				1
start loss						0
frameshift	1 clinvar					1
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	1	1	35	10	1	48

Highest pathogenic variant AF is 0.0000020707391

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 55 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005536.4	RefSeq	NP_005527.1	8	MANE Select
ENST00000256108.10	Ensembl	ENSP00000256108.5	8	MANE Select
NM_001144878.2	RefSeq	NP_001138350.1	9	Standard
NM_001144879.2	RefSeq	NP_001138351.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Inositol phosphate metabolism - Homo sapiens (human)
Phosphatidylinositol signaling system - Homo sapiens (human)
Inositol Phosphate Metabolism
Inositol Metabolism
Integrated Breast Cancer Pathway

Biological Process

inositol biosynthetic process
phosphatidylinositol biosynthetic process
phosphate-containing compound metabolic process
signal transduction
inositol phosphate metabolic process

Molecular Function

magnesium ion binding
protein binding
inositol monophosphate 1-phosphatase activity
manganese ion binding
lithium ion binding

Cellular Component

cytoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000449740
Coding exons: 9
Length: 28733
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125738
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.435	157	173	0.907	0.00000816	2183
Missense (PolyPhen)		44	63.075	0.69758		775
Synonymous	0.718	50	56.9	0.879	0.00000299	651
Loss of Function	1.93	8	16.5	0.486	7.93e-7	211

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000053	0.000053	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Responsible for the provision of inositol required for synthesis of phosphatidylinositol and polyphosphoinositides and has been implicated as the pharmacological target for lithium action in brain. Has broad substrate specificity and can use myo- inositol monophosphates, myo-inositol 1,3-diphosphate, myo- inositol 1,4-diphosphate, scyllo-inositol-phosphate, D-galactose 1-phosphate, glucose-1-phosphate, glucose-6-phosphate, fructose-1- phosphate, beta-glycerophosphate, and 2'-AMP as substrates. {ECO:0000269|PubMed:17068342, ECO:0000269|PubMed:8718889, ECO:0000269|PubMed:9462881}.;
Disease: DISEASE: Mental retardation, autosomal recessive 59 (MRT59) [MIM:617323]: A form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT59 transmission pattern is consistent with autosomal recessive inheritance. {ECO:0000269|PubMed:26416544}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.390

Intolerance Scores

LoFtool: 0.832
RVIS EVS: 0.35
RVIS percentile EVS: 74.18

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.985

Gene Damage Prediction

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