AUTS2

protein-coding

activator of transcription and developmental regulator AUTS2

Gene summary

This gene has been implicated in neurodevelopment and as a candidate gene for numerous neurological disorders, including autism spectrum disorders, intellectual disability, and developmental delay. Mutations in this gene have also been associated with non-neurological disorders, such as acute lymphoblastic leukemia, aging of the skin, early-onset androgenetic alopecia, and certain cancers. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2014]

MANE transcript

NM_015570.4

Inheritance

ClinVar variants

P:111U:527B:420

Top phenotype

Intellectual developmental disorder, autosomal dominant 26

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr7:69,598,296-70,793,506

External References & Databases

Ensembl (ENSG00000158321)

Transcript & Mutation Effects

hg38 • Region Span ~1,195.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autism spectrum disorder due to AUTS2 deficiencyDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014361

Submitter: G2P

autism spectrum disorder due to AUTS2 deficiencySUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014361

Submitter: Orphanet

autism spectrum disorder due to AUTS2 deficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014361

Submitter: PanelApp Australia

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

Variants in the AUTS2 gene were first reported in multiple individuals with syndromic intellectual disability in 2013 (Beunders et al. 2013, PMID: 23332918). Affected individuals present with intellectual disability, microcephaly, feeding problems, and mild dysmorphic features. Numerous variants including genomic rearrangements, whole-gene deletions, intragenic deletions and duplications, and loss of function sequence variants have been described (PMID: 22872102, 23650183, 26545289, and 24459036). The mechanism for disease is haploinsufficiency. This gene-disease relationship is supported by animal models, rescue experiments, and expression studies. In summary, AUTS2 is definitively associated with syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Working Group on 09/01/2020 (SOP Version 7).

autism spectrum disorder due to AUTS2 deficiencySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014361

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal dominant 26AD

Manifestation: Craniofacial; 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: 22872102; 23332918; 25205402

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AUTS2 variants in ClinVar

21 Conditions Cataloged

not providedTotal: 986

Inborn genetic diseasesTotal: 197

Autism spectrum disorder due to AUTS2 deficiencyTotal: 152

AUTS2-related disorderTotal: 83

not specifiedTotal: 41

Intellectual disabilityTotal: 12

Autism spectrum disorderTotal: 6

See casesTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015570.4. 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			9 clinvar	226 clinvar	18 clinvar	253
missense	3 clinvar	12 clinvar	499 clinvar	137 clinvar	37 clinvar	688
nonsense	14 clinvar	11 clinvar	3 clinvar	1 clinvar		29
start loss	3 clinvar	1 clinvar				4
frameshift	35 clinvar	17 clinvar	8 clinvar	1 clinvar		61
splice donor/acceptor (+/-2bp)	8 clinvar	7 clinvar	8 clinvar			23
Total	63	48	527	365	55	1058

Highest pathogenic variant AF is 0.000008673418

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 57 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015570.4	RefSeq	NP_056385.1	19	MANE Select
ENST00000342771.10	Ensembl	ENSP00000344087.4	19	MANE Select
NM_001127231.3	RefSeq	NP_001120703.1	18	Standard
NM_001127232.3	RefSeq	NP_001120704.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
auts2a	Danio rerio	Structure: motor neuron Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

auts2a

Danio rerio

Structure: motor neuron

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gene expression (Transcription)
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known
Generic Transcription Pathway
RNA Polymerase II Transcription
Transcriptional regulation by RUNX1

Biological Process

neuron migration
biological_process
positive regulation of lamellipodium assembly
forebrain neuron development
actin cytoskeleton reorganization

Molecular Function

molecular_function
chromatin binding
protein binding

Cellular Component

cellular_component
nucleus
cytoplasm
actin cytoskeleton
growth cone

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000342771
Coding exons: 19
Length: 1194150
Individuals with no LoFs: 125742
Homozygous LoFs: 0
Heterozygous LoFs: 6
Defined: 125748
p: 0.0000239

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.22	617	793	0.778	0.0000512	8156
Missense (PolyPhen)		253	375.2	0.67431		3698
Synonymous	-1.17	362	335	1.08	0.0000233	2614
Loss of Function	5.78	7	52.0	0.135	0.00000292	553

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000036	0.000035	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of a Polycomb group (PcG) multiprotein PRC1- like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A 'Lys-119', rendering chromatin heritably changed in its expressibility (PubMed:25519132). The PRC1-like complex that contains PCGF5, RNF2, CSNK2B, RYBP and AUTS2 has decreased histone H2A ubiquitination activity, due to the phosphorylation of RNF2 by CSNK2B (PubMed:25519132). As a consequence, the complex mediates transcriptional activation (PubMed:25519132). In the cytoplasm, plays a role in axon and dendrite elongation and in neuronal migration during embryonic brain development. Promotes reorganization of the actin cytoskeleton, lamellipodia formation and neurite elongation via its interaction with RAC guanine nucleotide exchange factors, which then leads to the activation of RAC1 (By similarity). {ECO:0000250|UniProtKB:A0A087WPF7, ECO:0000269|PubMed:25519132}.;
Disease: DISEASE: Mental retardation, autosomal dominant 26 (MRD26) [MIM:615834]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Additional MRD26 features include autism, short stature, microcephaly, cerebral palsy, and facial dysmorphisms. {ECO:0000269|PubMed:23332918}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.317
RVIS EVS: -1.97
RVIS percentile EVS: 1.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0988

Gene Damage Prediction

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