AAAS

protein-coding

aladin WD repeat nucleoporin, the group of WD repeat domain containing|Nucleoporins

Gene summary

The protein encoded by this gene is a member of the WD-repeat family of regulatory proteins and may be involved in normal development of the peripheral and central nervous system. The encoded protein is part of the nuclear pore complex and is anchored there by NDC1. Defects in this gene are a cause of achalasia-addisonianism-alacrima syndrome (AAAS), also called triple-A syndrome or Allgrove syndrome. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

MANE transcript

NM_015665.6

Inheritance

ClinVar variants

P:109U:135B:150

Top phenotype

Achalasia-addisonianism-alacrimia syndrome

gnomAD constraint

pLI —, LoF o/e 0.71

Max pathogenic AF

—

Genomic locus

chr12:53,307,456-53,324,864

External References & Databases

Ensembl (ENSG00000094914)

Transcript & Mutation Effects

hg38 • Region Span ~17.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

triple-A syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009279

Submitter: G2P

triple-A syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009279

Submitter: PanelApp Australia

triple-A syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009279

Submitter: Labcorp Genetics (formerly Invitae)

triple-A syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009279

Submitter: Ambry Genetics

triple-A syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009279

Submitter: Orphanet

Clinical Genomic Database (CGD)

Achalasia-addisonianism-alacrimia syndromeAR

Manifestation: Dermatologic; Endocrine; Gastrointestinal; Neurologic; Ophthalmologic

Intervention: Endocrine

Rationale: Surveillance and treatment/preventive measures (with substitution therapy) to avoid sequelae of adrenal insufficiency, including adrenal crisis, may be beneficial

Refs: 78049; 6243664; 3565479; 1537368; 8006362; 7895750; 8757578; 11062474; 11159947; 11914417; 12429595; 12752575; 16264411; 16938764; 8628786; 19172511; 18172684; 20051279; 20200814; 20499090; 20447142; 21565631

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AAAS variants in ClinVar

12 Conditions Cataloged

not providedTotal: 425

Glucocorticoid deficiency with achalasiaTotal: 95

Inborn genetic diseasesTotal: 87

not specifiedTotal: 21

AAAS-related disorderTotal: 19

Achalasia-alacrima syndromeTotal: 2

Abnormality of the nervous systemTotal: 1

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015665.6. 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				137 clinvar	3 clinvar	140
missense	4 clinvar	10 clinvar	129 clinvar	10 clinvar		153
nonsense	23 clinvar	4 clinvar	1 clinvar			28
start loss		1 clinvar				1
frameshift	24 clinvar	13 clinvar	2 clinvar			39
splice donor/acceptor (+/-2bp)	7 clinvar	23 clinvar	3 clinvar			33
Total	58	51	135	147	3	394

Highest pathogenic variant AF is 0.00015984022

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015665.6	RefSeq	NP_056480.1	16	MANE Select
ENST00000209873.9	Ensembl	ENSP00000209873.4	16	MANE Select
NM_001173466.2	RefSeq	NP_001166937.1	15	Standard
ENST00000394384.7	Ensembl	ENSP00000377908.3	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RNA transport - Homo sapiens (human)
tRNA processing
Disease
Gene expression (Transcription)
Regulation of HSF1-mediated heat shock response

Biological Process

mRNA export from nucleus
nucleocytoplasmic transport
learning
fertilization
viral process

Molecular Function

molecular_function

Cellular Component

nucleus
nuclear envelope
nuclear pore
nucleoplasm
centrosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000209873
Coding exons: 16
Length: 17409
Individuals with no LoFs: 125582
Homozygous LoFs: 0
Heterozygous LoFs: 166
Defined: 125748
p: 0.000660

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.363	316	298	1.06	0.0000175	3476
Missense (PolyPhen)		80	77.742	1.0291		947
Synonymous	0.239	114	117	0.972	0.00000618	1175
Loss of Function	1.61	25	35.3	0.707	0.00000224	341

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0023	0.0023	notable
Latino/Admixed American	0.00075	0.00069	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00022	0.00022	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00067	0.00067	rare
South Asian	0.00065	0.00065	rare
Other	0.00065	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Plays a role in the normal development of the peripheral and central nervous system.;

Intolerance Scores

LoFtool: 0.178
RVIS EVS: -0.91
RVIS percentile EVS: 9.96

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.538

Gene Damage Prediction

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