IER3IP1

Chr 18AR

immediate early response 3 interacting protein 1

Also known as: HSPC039, MEDS, PRO2309

NCBI Gene: 51124 ENSG00000134049 UniProt: Q9Y5U9 OMIM: 609382

This protein regulates endoplasmic reticulum secretion and is required for secretion of extracellular matrix proteins necessary for brain development and neural progenitor proliferation. Mutations cause microcephaly, epilepsy, and diabetes syndrome through autosomal recessive inheritance. The gene shows low constraint to loss-of-function variation, consistent with a recessive disorder pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Microcephaly, epilepsy, and diabetes syndromeMIM #614231

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Microcephaly, epilepsy, and diabetes syndrome; no ClinGen or GenCC tier

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.41

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.41LOEUF

pLI 0.023

Z-score 0.95

OE 0.56 (0.25–1.41)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.39Z-score

OE missense 1.17 (0.93–1.48)

50 obs / 42.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.56 (0.25–1.41)

0≤0.351.4

Missense OE?1.17 (0.93–1.48)

0≤0.61.4

Synonymous OE?1.37

0≤1.21.6

LoF obs/exp: 3 / 5.4Missense obs/exp: 50 / 42.8Syn Z: -1.23

Background carrier burden — how many people carry a rare variant somewhere in IER3IP1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 640

108 rare PASS variants

Rare truncating (LoF)

1 in 8,200

31 rare PASS variants

Rare synonymous (reference)

1 in 1,300

47 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for IER3IP1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 910	1 in 7,500
South Asian	~43k	1 in 580	≈ 1 in 21,000
Remaining (unassigned)	~30k	1 in 470	≈ 1 in 29,000
European (Finnish)	~27k	1 in 5,300	≈ 1 in 13,000
Admixed American	~22k	1 in 500	1 in 4,500
African / African American	~21k	1 in 1,800	≈ 1 in 8,400
East Asian	~20k	1 in 1,400	≈ 1 in 20,000
Ashkenazi Jewish	~13k	≈ 1 in 13,000	none seen
Middle Eastern	~2,884	≈ 1 in 950	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 2 of 3 coding exons well covered in gnomAD exomes; exon 3 marginal. Genomes: all 3.? see exons ↓