GeneBe

ARMC5

protein-coding

armadillo repeat containing 5, the group of Armadillo repeat containing

Gene summary

This gene encodes a member of the ARM (armadillo/beta-catenin-like repeat) superfamily. The ARM repeat is a tandemly repeated sequence motif with approximately 40 amino acid long. This repeat is implicated in mediating protein-protein interactions. The encoded protein contains seven ARM repeats. Mutations in this gene are associated with primary bilateral macronodular adrenal hyperplasia, which is also known as ACTH-independent macronodular adrenal hyperplasia 2. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2014]

MANE transcript

NM_001105247.2

Inheritance

AD

ClinVar variants

P:41U:176B:115

Top phenotype

ACTH-independent macronodular adrenal hyperplasia 2

gnomAD constraint

pLI —, LoF o/e 0.26

Max pathogenic AF

—

Genomic locus

chr16:31,458,080-31,467,166

External References & Databases

Ensembl (ENSG00000140691)NCBI Gene (79798)OMIM (615549)HGNC:25781GenCCUniProt (Q96C12)AlphaFoldClinVar (ARMC5)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~9.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Cushing syndrome due to macronodular adrenal hyperplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0009049

Submitter: Orphanet

ACTH-independent macronodular adrenal hyperplasia 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014416

Submitter: Genomics England PanelApp

ACTH-independent macronodular adrenal hyperplasia 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014416

Submitter: Ambry Genetics

ACTH-independent macronodular adrenal hyperplasia 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014416

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

ACTH-independent macronodular adrenal hyperplasia 2AD

Manifestation: Endocrine; Oncologic

Intervention: Endocrine; Oncologic

Rationale: Surveillance for neoplasms, can allow early detection and treatment, which can involve surgical excision of the neoplasm or medical management (eg, targeting aberrant receptor expression) to control cortisol production

Comments: Germline variants in this tumor suppressor gene may result in the clinical phenotype in the presence of a second, somatic variant

Refs: 19018784; 24283224; 24601692; 24708098; 24905064Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ARMC5 variants in ClinVar

8 Conditions Cataloged
Inborn genetic diseasesTotal: 142
ARMC5-related disorderTotal: 108
not providedTotal: 84
not specifiedTotal: 55
ACTH-independent macronodular adrenal hyperplasia 2Total: 39
Cushing syndrome due to macronodular adrenal hyperplasiaTotal: 1
Hereditary cancer-predisposing syndromeTotal: 1
Macronodular adrenal hyperplasiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001105247.2. 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.

EffectPLPVUSLBBSum
synonymous
76
clinvar
8
clinvar
 84
missense
2
clinvar
7
clinvar
171
clinvar
29
clinvar
2
clinvar
 211
nonsense
5
clinvar
6
clinvar
1
clinvar
 12
start loss
0
frameshift
9
clinvar
11
clinvar
1
clinvar
 21
splice donor/acceptor (+/-2bp)
1
clinvar
3
clinvar
 4
Total162517610510332

Highest pathogenic variant AF is 0.000019708317

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 19 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001105247.2RefSeqNP_001098717.16MANE Select
ENST00000268314.9EnsemblENSP00000268314.46MANE Select
NM_001288767.2RefSeqNP_001275696.18Standard
NM_001301820.1RefSeqNP_001288749.17Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cushing,s syndrome - Homo sapiens (human)

Cellular Component

  • nucleoplasm
  • cytoplasm
  • cytosol
  • focal adhesion

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000268314
Coding exons
6
Length
9087
Individuals with no LoFs
124838
Homozygous LoFs
0
Heterozygous LoFs
16
Defined
124854
p
0.0000641
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.714765930.8030.00003935660
Missense (PolyPhen)135243.760.553832355
Synonymous-2.213192731.170.00001692291
Loss of Function3.54726.80.2620.00000149268

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000200.00019rare
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian0.0000560.000056rare
Finnish0.0000490.000046rare
European (Non-Finnish)0.0000630.000062rare
South Asian0.0000330.000033rare
Other0.000170.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Involved in fetal development, T-cell function and adrenal gland growth homeostasis (By similarity). Negatively regulates adrenal cells survival. Plays a role in steroidogenesis, modulates steroidogenic enzymes expression and cortisol production (PubMed:24283224, PubMed:28676429). {ECO:0000250|UniProtKB:Q5EBP3, ECO:0000269|PubMed:24283224, ECO:0000269|PubMed:28676429}.;
Disease
DISEASE: ACTH-independent macronodular adrenal hyperplasia 2 (AIMAH2) [MIM:615954]: A form of macronodular adrenal hyperplasia characterized by multiple, bilateral, non-pigmented, benign, adrenocortical nodules. It results in excessive production of cortisol leading to ACTH-independent Cushing syndrome. Clinical manifestations of Cushing syndrome include facial and truncal obesity, abdominal striae, muscular weakness, osteoporosis, arterial hypertension, diabetes. {ECO:0000269|PubMed:24283224, ECO:0000269|PubMed:24601692, ECO:0000269|PubMed:24708098, ECO:0000269|PubMed:24905064, ECO:0000269|PubMed:25822102, ECO:0000269|PubMed:25853793, ECO:0000269|PubMed:26604299, ECO:0000269|PubMed:27094308, ECO:0000269|PubMed:28458897, ECO:0000269|PubMed:28676429}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool
0.454
RVIS EVS
0.25
RVIS percentile EVS
69.69

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.443

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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