ASPM

protein-coding

assembly factor for spindle microtubules

Gene summary

This gene is the human ortholog of the Drosophila melanogaster 'abnormal spindle' gene (asp), which is essential for normal mitotic spindle function in embryonic neuroblasts. Studies in mouse also suggest a role of this gene in mitotic spindle regulation, with a preferential role in regulating neurogenesis. Mutations in this gene are associated with microcephaly primary type 5. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, May 2011]

Previous symbols:

MCPH5

MANE transcript

NM_018136.5

Inheritance

ClinVar variants

P:360U:1039B:533

Top phenotype

Microcephaly, primary autosomal recessive, 5

gnomAD constraint

pLI —, LoF o/e 0.63

Max pathogenic AF

—

Genomic locus

chr1:197,084,121-197,146,694

External References & Databases

Ensembl (ENSG00000066279)

Transcript & Mutation Effects

hg38 • Region Span ~62.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly 5, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012106

Submitter: PanelApp Australia

microcephaly 5, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012106

Submitter: Labcorp Genetics (formerly Invitae)

microcephaly 5, primary, autosomal recessiveDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0012106

Submitter: G2P

autosomal recessive primary microcephalyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: ClinGen

ASPM was first reported in relation to autosomal recessive microcephaly in 2002 (Bond et al., PMID: 12355089). 10 variants (nonsense, frameshift) that have been reported in over 15 probands in 5 publications (PMIDs: 12355089, 15355437, 16141009, 18452193, 19332161) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (expression-level evidence, mouse model, and ferret model; PMIDs: 15972725, 20823249, 29643508). Expression analysis in human cells shows that ASPM is localized, along with chromosomal DNA, at the spindle poll during cell division. Both the mouse and ferret mutants recapitulate the human phenotype of microcephaly. In summary, there is definitive evidence supporting the relationship between ASPM and autosomal recessive microcephaly. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Brain Malformations GCEP on the meeting date 3/12/2024 (SOP Version 10).

autosomal recessive primary microcephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: Orphanet

Clinical Genomic Database (CGD)

Microcephaly, primary autosomal recessive, 5AR

Manifestation: 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

Comments: Frequent infections have been described, but it is not clear if these are intrinsic to the disorder or secondary to neurologic manifestations

Refs: 12355089; 14574646; 16673149; 18452193; 19353628; 19028728; 19770472

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ASPM variants in ClinVar

16 Conditions Cataloged

not providedTotal: 1399

Microcephaly 5, primary, autosomal recessiveTotal: 680

Inborn genetic diseasesTotal: 644

not specifiedTotal: 196

ASPM-related disorderTotal: 67

Intellectual disabilityTotal: 17

Autosomal recessive primary microcephalyTotal: 16

Microcephaly 1, primary, autosomal recessiveTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018136.5. 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	1 clinvar	1 clinvar	33 clinvar	340 clinvar	6 clinvar	381
missense	3 clinvar	2 clinvar	965 clinvar	175 clinvar	11 clinvar	1156
nonsense	105 clinvar	27 clinvar	10 clinvar	1 clinvar		143
start loss		1 clinvar	1 clinvar			2
frameshift	149 clinvar	50 clinvar	22 clinvar			221
splice donor/acceptor (+/-2bp)	6 clinvar	15 clinvar	8 clinvar			29
Total	264	96	1039	516	17	1932

Highest pathogenic variant AF is 0.00018485979

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018136.5	RefSeq	NP_060606.3	28	MANE Select
ENST00000367409.9	Ensembl	ENSP00000356379.4	28	MANE Select
NM_001206846.2	RefSeq	NP_001193775.1	27	Standard
ENST00000294732.11	Ensembl	ENSP00000294732.7	27	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
aspm	Danio rerio	Structure: head Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

aspm

Danio rerio

Structure: head

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

neuron migration
positive regulation of neuroblast proliferation
spindle organization
spermatogenesis
male gonad development

Molecular Function

calmodulin binding
protein kinase binding

Cellular Component

nucleus
cytoplasm
centrosome
apical plasma membrane
midbody

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000367409
Coding exons: 28
Length: 62567
Individuals with no LoFs: 124805
Homozygous LoFs: 5
Heterozygous LoFs: 938
Defined: 125748
p: 0.00376

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.736	1836	1.75e+3	1.05	0.0000910	22782
Missense (PolyPhen)		460	507.5	0.90641		6929
Synonymous	-3.29	682	581	1.17	0.0000281	6448
Loss of Function	4.39	105	166	0.632	0.00000997	2088

Population LoF Frequency

Population	CAF	p-value	Status
African	0.032	0.031	notable
Latino/Admixed American	0.0033	0.0033	notable
Ashkenazi Jewish	0.00080	0.00079	rare
East Asian	0.0014	0.0014	notable
Finnish	0.00089	0.00088	rare
European (Non-Finnish)	0.0021	0.0021	notable
South Asian	0.00092	0.00091	rare
Other	0.0021	0.0021	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in mitotic spindle regulation and coordination of mitotic processes. The function in regulating microtubule dynamics at spindle poles including spindle orientation, astral microtubule density and poleward microtubule flux seems to depend on the association with the katanin complex formed by KATNA1 and KATNB1. Enhances the microtubule lattice severing activity of KATNA1 by recruiting the katanin complex to microtubules. Can block microtubule minus-end growth and reversely this function can be enhanced by the katanin complex (PubMed:28436967). May have a preferential role in regulating neurogenesis. {ECO:0000269|PubMed:12355089, ECO:0000269|PubMed:15972725, ECO:0000269|PubMed:28436967}.;
Disease: DISEASE: Microcephaly 5, primary, autosomal recessive (MCPH5) [MIM:608716]: A disease defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Affected individuals are mentally retarded. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits due to degenerative brain disorder. {ECO:0000269|PubMed:12355089, ECO:0000269|PubMed:14574646, ECO:0000269|PubMed:22989186}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0867

Intolerance Scores

LoFtool: 0.984
RVIS EVS: 1.76
RVIS percentile EVS: 96.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.650

Gene Damage Prediction

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