ANXA5

Chr 4AD

annexin A5

Also known as: ANX5, CPB-I, ENX2, HEL-S-7, PP4, RPRGL3, VAC-alph

NCBI Gene: 308 ENSG00000164111 UniProt: P08758 OMIM: 131230

Annexin 5 is a calcium-dependent phospholipid binding protein that functions as an anticoagulant by indirectly inhibiting the thromboplastin-specific complex in the blood coagulation cascade. Mutations cause autosomal dominant susceptibility to recurrent pregnancy loss. The gene shows very low constraint against loss-of-function variants (pLI near zero), suggesting that complete loss of function may be tolerated.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The Annexin 5 gene spans 29 kb containing 13 exons, and encodes a single transcript of approximately 1.6 kb and a protein product with a molecular weight of about 35 kDa.The protein encoded by this gene belongs to the annexin family of calcium-dependent phospholipid binding proteins some of which have been implicated in membrane-related events along exocytotic and endocytotic pathways. Annexin 5 is a phospholipase A2 and protein kinase C inhibitory protein with calcium channel activity and a potential role in cellular signal transduction, inflammation, growth and differentiation. Annexin 5 has also been described as placental anticoagulant protein I, vascular anticoagulant-alpha, endonexin II, lipocortin V, placental protein 4 and anchorin CII. Polymorphisms in this gene have been implicated in various obstetric complications. [provided by RefSeq, Dec 2019]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Pregnancy loss, recurrent, susceptibility to, 3}MIM #614391

Active trials

102

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.45

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.45LOEUF

pLI 0.000

Z-score -0.06

OE 1.01 (0.72–1.45)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.55Z-score

OE missense 0.88 (0.77–1.01)

149 obs / 169.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.01 (0.72–1.45)

0≤0.351.4

Missense OE?0.88 (0.77–1.01)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 22 / 21.7Missense obs/exp: 149 / 169.2Syn Z: 0.26

Background carrier burden — how many people carry a rare variant somewhere in ANXA5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 150

376 rare PASS variants

Rare truncating (LoF)

1 in 590

85 rare PASS variants

Rare synonymous (reference)

1 in 310

124 rare PASS variants

Rare missense and truncating variants are carried at similar rates in ANXA5; this gene does not show strong loss-of-function constraint by this measure. 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 120	1 in 680
South Asian	~43k	1 in 170	1 in 430
Remaining (unassigned)	~30k	1 in 170	1 in 440
European (Finnish)	~27k	1 in 420	1 in 820
Admixed American	~22k	1 in 190	1 in 1,500
African / African American	~21k	1 in 130	1 in 750
East Asian	~20k	1 in 130	1 in 2,000
Ashkenazi Jewish	~13k	1 in 2,600	none seen
Middle Eastern	~2,884	1 in 170	≈ 1 in 2,900

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): 9 of 12 coding exons well covered in gnomAD exomes; exons 2, 5, 11 marginal. Genomes: all 12.? see exons ↓