IER3IP1

protein-coding

immediate early response 3 interacting protein 1

Gene summary

This gene encodes a small protein that is localized to the endoplasmic reticulum (ER) and may play a role in the ER stress response by mediating cell differentiation and apoptosis. Transcription of this gene is regulated by tumor necrosis factor alpha and specificity protein 1 (Sp1). Mutations in this gene may play a role in microcephaly, epilepsy, and diabetes syndrome (MEDS), and a pseudogene of this gene is located on the long arm of chromosome 12. [provided by RefSeq, Dec 2011]

MANE transcript

NM_016097.5

Inheritance

ClinVar variants

P:1U:48B:33

Top phenotype

Microcephaly, epilepsy, and diabetes syndrome 1

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr18:47,152,834-47,176,364

External References & Databases

Ensembl (ENSG00000134049)

Transcript & Mutation Effects

hg38 • Region Span ~23.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

primary microcephaly-epilepsy-permanent neonatal diabetes syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013647

Submitter: PanelApp Australia

primary microcephaly-epilepsy-permanent neonatal diabetes syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013647

Submitter: Orphanet

microcephaly, epilepsy, and diabetes syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0031481

Submitter: Labcorp Genetics (formerly Invitae)

primary microcephaly-epilepsy-permanent neonatal diabetes syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013647

Submitter: Genomics England PanelApp

microcephaly, epilepsy, and diabetes syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0031481

Submitter: G2P

Clinical Genomic Database (CGD)

Microcephaly, epilepsy, and diabetes syndrome 1AR

Manifestation: Endocrine; Neurologic

Intervention: Endocrine

Rationale: Among other findings, individuals may have early-onset diabetes, which may be difficult to control, and awareness may allow early diagnosis and medical management

Comments: Individuals may have early-onset diabetes, which may be difficult to control

Refs: 16972080; 21835305; 24138066

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to IER3IP1 variants in ClinVar

6 Conditions Cataloged

Microcephaly, epilepsy, and diabetes syndromeTotal: 96

Inborn genetic diseasesTotal: 14

not providedTotal: 8

Microcephaly, epilepsy, and diabetes syndrome 1Total: 7

not specifiedTotal: 5

IER3IP1-related disorderTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_016097.5. 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				33 clinvar		33
missense		1 clinvar	40 clinvar			41
nonsense			2 clinvar			2
start loss			2 clinvar			2
frameshift			3 clinvar			3
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	1	48	33	0	82

Highest pathogenic variant AF is 0.000001918443

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_016097.5	RefSeq	NP_057181.1	3	MANE Select
ENST00000256433.6	Ensembl	ENSP00000256433.3	3	MANE Select
ENST00000639845.1	Ensembl	ENSP00000491049.1	2	Standard
ENST00000639845.2	Ensembl	ENSP00000491049.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ier3ip1	Danio rerio	Structure: blood cell Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

ier3ip1

Danio rerio

Structure: blood cell

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

endoplasmic reticulum to Golgi vesicle-mediated transport
regulation of fibroblast apoptotic process

Cellular Component

endoplasmic reticulum
endoplasmic reticulum membrane
Golgi apparatus
membrane
COPII-coated ER to Golgi transport vesicle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000256433
Coding exons: 3
Length: 21333
Individuals with no LoFs: 125743
Homozygous LoFs: 0
Heterozygous LoFs: 4
Defined: 125747
p: 0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.392	50	42.8	1.17	0.00000212	504
Missense (PolyPhen)		11	14.839	0.74127		181
Synonymous	-1.23	25	18.3	1.37	9.92e-7	175
Loss of Function	0.953	3	5.39	0.557	2.95e-7	51

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000032	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be implicated in the regulation of apoptosis. May be involved in protein transport between endoplasmic reticulum and Golgi apparatus (By similarity). {ECO:0000250}.;

Intolerance Scores

LoFtool: 0.516
RVIS EVS: 0.26
RVIS percentile EVS: 69.83

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.539

Gene Damage Prediction

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