ANXA11

protein-coding

annexin A11, the group of Annexins

Gene summary

This gene encodes a member of the annexin family, a group of calcium-dependent phospholipid-binding proteins. Annexins have unique N-terminal domains and conserved C-terminal domains, which contain calcium-dependent phospholipid-binding sites. The encoded protein is a 56-kD antigen recognized by sera from patients with various autoimmune diseases. Several transcript variants encoding two different isoforms have been identified. [provided by RefSeq, Dec 2015]

Previous symbols:

ANX11

MANE transcript

NM_145868.2

Inheritance

ClinVar variants

P:6U:245B:99

Top phenotype

Amytrophic lateral sclerosis 23; Inclusion body myopathy and brain white matter abnormalities

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr10:80,150,889-80,205,572

External References & Databases

Ensembl (ENSG00000122359)

Transcript & Mutation Effects

hg38 • Region Span ~54.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

inclusion body myopathy and brain white matter abnormalitiesLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0850514

Submitter: Labcorp Genetics (formerly Invitae)

amyotrophic lateral sclerosis type 23STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0027694

Submitter: Labcorp Genetics (formerly Invitae)

inclusion body myopathy and brain white matter abnormalitiesMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0850514

Submitter: Ambry Genetics

amyotrophic lateral sclerosis type 23STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0027694

Submitter: Genomics England PanelApp

amyotrophic lateral sclerosis type 23DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0027694

Submitter: ClinGen

ANXA11 was first reported in relation to autosomal dominant amyotrophic lateral sclerosis (ALS) in 2017 (Smith et al., PMID: 28469040). 32 variants have been reported in ALS patients in the literature, 20 of which were sufficiently rare in the general population and scored as part of this curation. This includes 17 missense variants and three splicing variants that have been reported in 11 publications (PMIDs: 28469040, 29845112, 30054183, 30337194, 33218681, 33618928, 34048612, 34099057, 29650794, 33589474, 33087501). Eight of these variants also had supporting functional data. Four variants were reported in multiple publications, with their second observation also scored to reach the maximum score for genetic evidence of 12 pts. The mechanism of pathogenicity appears to be gain of function. This gene-disease association is also supported by experimental evidence including expression studies, functional alterations in patient cells, rescue experiments in vitro and protein interactions (PMIDs: 28469040, 33218681, 34099057, 33087501). Notably, this includes the observation of ubiquitinated neuronal cytoplasmic inclusions positive for the ANXA11 protein with co-localisation with TDP-43 and p62 in post-mortem neuronal tissues from patients carrying three different ANXA11 variants. In summary, ANXA11 is definitively associated with autosomal dominant ALS. This has been repeatedly demonstrated in both the research, and has been upheld over time. This classification was approved by the ClinGen ALS GCEP on November 9, 2021 (SOP Version 8).

amyotrophic lateral sclerosisSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Orphanet

amyotrophic lateral sclerosis type 23MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0027694

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Amytrophic lateral sclerosis 23; Inclusion body myopathy and brain white matter abnormalitiesAD

Manifestation: Musculoskeletal; 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: 28469040; 34048612

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ANXA11 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 343

Inborn genetic diseasesTotal: 85

ANXA11-related disorderTotal: 85

not specifiedTotal: 29

Amyotrophic lateral sclerosis type 23Total: 19

Inclusion body myopathy and brain white matter abnormalitiesTotal: 11

Amyotrophic lateral sclerosisTotal: 5

Oculopharyngeal muscular dystrophy 1Total: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_145868.2. 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			5 clinvar	70 clinvar	7 clinvar	82
missense	2 clinvar	3 clinvar	212 clinvar	16 clinvar	5 clinvar	238
nonsense			8 clinvar			8
start loss			1 clinvar			1
frameshift			10 clinvar	1 clinvar		11
splice donor/acceptor (+/-2bp)	1 clinvar		9 clinvar			10
Total	3	3	245	87	12	350

Highest pathogenic variant AF is 0.000074799864

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 144 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_145868.2	RefSeq	NP_665875.1	14	MANE Select
ENST00000422982.8	Ensembl	ENSP00000404412.2	14	MANE Select
NM_001157.3	RefSeq	NP_001148.1	14	Standard
NM_001278407.2	RefSeq	NP_001265336.1	14	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Biological Process

phagocytosis
cytokinetic process
response to calcium ion

Molecular Function

RNA binding
calcium ion binding
protein binding
calcium-dependent phospholipid binding
phosphatidylethanolamine binding

Cellular Component

nuclear envelope
nucleoplasm
cytoplasm
spindle
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000438331
Coding exons: 14
Length: 54684
Individuals with no LoFs: 125677
Homozygous LoFs: 0
Heterozygous LoFs: 71
Defined: 125748
p: 0.000282

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.249	311	299	1.04	0.0000179	3197
Missense (PolyPhen)		118	123.95	0.95202		1243
Synonymous	-0.0192	121	121	1.00	0.00000772	1023
Loss of Function	1.64	19	28.5	0.668	0.00000153	316

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00044	0.00043	rare
Latino/Admixed American	0.00067	0.00067	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00088	0.00087	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00016	0.00014	rare
South Asian	0.00024	0.00023	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Binds specifically to calcyclin in a calcium-dependent manner (By similarity). Required for midbody formation and completion of the terminal phase of cytokinesis. {ECO:0000250, ECO:0000269|PubMed:15197175}.;
Disease: DISEASE: Amyotrophic lateral sclerosis 23 (ALS23) [MIM:617839]: A form of amyotrophic lateral sclerosis, a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. ALS23 is an autosomal dominant form with incomplete penetrance. {ECO:0000269|PubMed:28469040}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.139

Intolerance Scores

LoFtool: 0.933
RVIS EVS: 0.49
RVIS percentile EVS: 79.61

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.978

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High