ALMS1

protein-coding

ALMS1 centrosome and basal body associated protein

Gene summary

This gene encodes a protein containing a large tandem-repeat domain as well as additional low complexity regions. The encoded protein functions in microtubule organization, particularly in the formation and maintanance of cilia. Mutations in this gene cause Alstrom syndrome. There is a pseudogene for this gene located adjacent in the same region of chromosome 2. Alternative splice variants have been described but their full length nature has not been determined. [provided by RefSeq, Apr 2014]

MANE transcript

NM_001378454.1

Inheritance

ClinVar variants

P:1068U:3148B:2763

Top phenotype

Alstrom syndrome

gnomAD constraint

pLI —, LoF o/e 0.75

Max pathogenic AF

—

Genomic locus

chr2:73,385,758-73,625,166

External References & Databases

Ensembl (ENSG00000116127)

Transcript & Mutation Effects

hg38 • Region Span ~239.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Alstrom syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008763

Submitter: Natera

Alstrom syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008763

Submitter: Genomics England PanelApp

Alstrom syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008763

Submitter: PanelApp Australia

Alstrom syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008763

Submitter: Labcorp Genetics (formerly Invitae)

Alstrom syndromeDEFINITIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0008763

Submitter: ClinGen

Alstrom syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008763

Submitter: G2P

Alstrom syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008763

Submitter: Orphanet

Clinical Genomic Database (CGD)

Alstrom syndromeAR

Manifestation: Audiologic/Otolaryngologic; Cardiovascular; Endocrine; Gastrointestinal; Ophthalmologic; Renal

Intervention: Audiologic/Otolaryngologic; Cardiovascular; Endocrine; Gastrointestinal; Ophthalmologic; Renal

Rationale: The condition may be recognizable from early manifestations (eg, related to visual loss), but dilated or restricted cardiomyopathy is common, and measures to decrease related morbidity and mortality may be beneficial; Management related to other sequelae, such as endocrine (eg, diabetes mellitus), renal, and hepatic manifestations, may also be beneficial; Recognition of hearing impairment can allow interventions related to speech and language development

Refs: 13649370; 5824738; 3766665; 3687707; 2231654; 1746604; 8418611; 8488920; 8636816; 9066877; 9409865; 9663233; 11343329; 11941369; 11941370; 17594715; 17850632; 22043170; 21522186; 20301444; 25864795

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ALMS1 variants in ClinVar

31 Conditions Cataloged

Alstrom syndromeTotal: 6232

Cardiovascular phenotypeTotal: 2401

not providedTotal: 1301

not specifiedTotal: 746

ALMS1-related disorderTotal: 671

Monogenic diabetesTotal: 68

Retinal dystrophyTotal: 50

Retinitis pigmentosaTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001378454.1. 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			68 clinvar	2156 clinvar	16 clinvar	2240
missense	6 clinvar	12 clinvar	3052 clinvar	566 clinvar	19 clinvar	3655
nonsense	226 clinvar	174 clinvar	8 clinvar	1 clinvar		409
start loss		7 clinvar				7
frameshift	351 clinvar	220 clinvar	11 clinvar	3 clinvar	2 clinvar	587
splice donor/acceptor (+/-2bp)	10 clinvar	62 clinvar	9 clinvar			81
Total	593	475	3148	2726	37	6979

Highest pathogenic variant AF is 0.00031846977

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001378454.1	RefSeq	NP_001365383.1	23	MANE Select
ENST00000613296.6	Ensembl	ENSP00000482968.1	23	MANE Select
NM_015120.4	RefSeq	NP_055935.4	23	Standard
ENST00000423048.5	Ensembl	ENSP00000399833.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
alms1	Danio rerio	Structure: pancreatic B cell Quality: decreased area abnormal

Gene / Model

Organism

Observed Phenotype

alms1

Danio rerio

Structure: pancreatic B cell

Quality: decreased area

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Regulation of PLK1 Activity at G2/M Transition
Recruitment of mitotic centrosome proteins and complexes
Loss of Nlp from mitotic centrosomes
Loss of proteins required for interphase microtubule organization from the centrosome
Centrosome maturation

Biological Process

G2/M transition of mitotic cell cycle
regulation of G2/M transition of mitotic cell cycle
endosomal transport
regulation of centriole replication
regulation of stress fiber assembly

Molecular Function

molecular_function
protein binding
alpha-actinin binding

Cellular Component

spindle pole
centrosome
centriole
cytosol
cilium

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000264448
Coding exons: 23
Length: 225035
Individuals with no LoFs: 125607
Homozygous LoFs: 0
Heterozygous LoFs: 141
Defined: 125748
p: 0.000561

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-2.99	2437	2.06e+3	1.19	0.000104	27075
Missense (PolyPhen)		670	594.06	1.1278		8851
Synonymous	-3.05	868	761	1.14	0.0000390	8368
Loss of Function	2.89	114	152	0.748	0.00000820	2008

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00071	0.00068	rare
Latino/Admixed American	0.00035	0.00035	rare
Ashkenazi Jewish	0.00030	0.00030	rare
East Asian	0.00061	0.00060	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00071	0.00069	rare
South Asian	0.00056	0.00056	rare
Other	0.00036	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in PCM1-dependent intracellular transport. Required, directly or indirectly, for the localization of NCAPD2 to the proximal ends of centrioles. Required for proper formation and/or maintenance of primary cilia (PC), microtubule-based structures that protrude from the surface of epithelial cells. {ECO:0000269|PubMed:17954613}.;
Disease: DISEASE: Alstrom syndrome (ALMS) [MIM:203800]: A rare autosomal recessive disorder characterized by progressive cone-rod retinal dystrophy, neurosensory hearing loss, early childhood obesity and diabetes mellitus type 2. Dilated cardiomyopathy, acanthosis nigricans, male hypogonadism, hypothyroidism, developmental delay and hepatic dysfunction can also be associated with the syndrome. {ECO:0000269|PubMed:11941369, ECO:0000269|PubMed:11941370}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.110

Intolerance Scores

LoFtool: 0.953
RVIS EVS: 2.29
RVIS percentile EVS: 98.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.0421

Gene Damage Prediction

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