MFGE8

Chr 15

milk fat globule EGF and factor V/VIII domain containing

Also known as: BA46, EDIL1, HMFG, HsT19888, MFG-E8, MFGM, OAcGD3S, SED1

NCBI Gene: 4240 ENSG00000140545 UniProt: Q08431 OMIM: 602281

The protein lactadherin promotes phagocytosis of apoptotic cells, maintains intestinal epithelial homeostasis, and supports mucosal healing and neovascularization. Mutations cause autosomal recessive primary immunodeficiency with gastrointestinal dysfunction, featuring recurrent infections and severe inflammatory bowel disease-like symptoms. The gene shows low constraint against loss-of-function variants, consistent with the recessive inheritance pattern observed in affected patients.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a preproprotein that is proteolytically processed to form multiple protein products. The major encoded protein product, lactadherin, is a membrane glycoprotein that promotes phagocytosis of apoptotic cells. This protein has also been implicated in wound healing, autoimmune disease, and cancer. Lactadherin can be further processed to form a smaller cleavage product, medin, which comprises the major protein component of aortic medial amyloid (AMA). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2015]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.90

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.90LOEUF

pLI 0.000

Z-score 1.90

OE 0.53 (0.33–0.90)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.36Z-score

OE missense 1.07 (0.96–1.19)

237 obs / 221.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.53 (0.33–0.90)

0≤0.351.4

Missense OE?1.07 (0.96–1.19)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 10 / 18.9Missense obs/exp: 237 / 221.7Syn Z: -0.92

Background carrier burden — how many people carry a rare variant somewhere in MFGE8?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 67

567 rare PASS variants

Rare truncating (LoF)

1 in 890

88 rare PASS variants

Rare synonymous (reference)

1 in 180

223 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MFGE8. 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 85	1 in 1,900
South Asian	~43k	1 in 78	1 in 590
Remaining (unassigned)	~30k	1 in 61	1 in 820
European (Finnish)	~27k	1 in 210	1 in 4,000
Admixed American	~22k	1 in 77	1 in 950
African / African American	~21k	1 in 82	1 in 1,700
East Asian	~20k	1 in 99	1 in 1,200
Ashkenazi Jewish	~13k	1 in 170	none seen
Middle Eastern	~2,884	1 in 69	≈ 1 in 960

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): 7 of 8 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 8.? see exons ↓