ATAD3A

protein-coding

ATPase family AAA domain containing 3A, the group of AAA ATPases

Gene summary

This gene encodes a ubiquitously expressed mitochondrial membrane protein that contributes to mitochondrial dynamics, nucleoid organization, protein translation, cell growth, and cholesterol metabolism. This gene is a member of the ATPase family AAA-domain containing 3 gene family which, in humans, includes two other paralogs. Naturally occurring mutations in this gene are associated with distinct neurological syndromes including Harel-Yoon syndrome. High-level expression of this gene is associated with poor survival in breast cancer patients. A homozygous knockout of the orthologous gene in mice results in embryonic lethality at day 7.5 due to growth retardation and defective development of the trophoblast lineage. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2017]

MANE transcript

NM_001170535.3

Inheritance

AD, AR, SD

ClinVar variants

P:32U:301B:92

Top phenotype

Harel-Yoon syndrome; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr1:1,512,162-1,534,685

External References & Databases

Ensembl (ENSG00000197785)

Transcript & Mutation Effects

hg38 • Region Span ~22.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Harel-Yoon syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014958

Submitter: G2P

Harel-Yoon syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014958

Submitter: G2P

Harel-Yoon syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014958

Submitter: Ambry Genetics

pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethalSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032931

Submitter: PanelApp Australia

Harel-Yoon syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014958

Submitter: Labcorp Genetics (formerly Invitae)

Harel-Yoon syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014958

Submitter: Labcorp Genetics (formerly Invitae)

Harel-Yoon syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014958

Submitter: PanelApp Australia

pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethalMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032931

Submitter: Ambry Genetics

Harel-Yoon syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014958

Submitter: Ambry Genetics

Harel-Yoon syndromeDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0014958

Submitter: Illumina

Clinical Genomic Database (CGD)

Harel-Yoon syndrome; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethalAD/AR

Manifestation: Biochemical; Cardiovascular; Craniofacial; Musculoskeletal; Ophthalmologic; Neurologic; Pulmonary

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: 27640307; 28549128; 29053797

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ATAD3A variants in ClinVar

14 Conditions Cataloged

not providedTotal: 226

Inborn genetic diseasesTotal: 187

not specifiedTotal: 123

Harel-Yoon syndromeTotal: 78

Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethalTotal: 39

Intellectual disabilityTotal: 5

ATAD3A-related disordersTotal: 3

Disorder of development or morphogenesisTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001170535.3. 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	5 clinvar	60 clinvar	4 clinvar	70
missense	2 clinvar	7 clinvar	282 clinvar	25 clinvar	3 clinvar	319
nonsense	1 clinvar	6 clinvar	4 clinvar			11
start loss		1 clinvar				1
frameshift	1 clinvar	7 clinvar	2 clinvar			10
splice donor/acceptor (+/-2bp)	1 clinvar	5 clinvar	8 clinvar			14
Total	5	27	301	85	7	425

Highest pathogenic variant AF is 0.000030359693

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001170535.3	RefSeq	NP_001164006.1	16	MANE Select
ENST00000378756.8	Ensembl	ENSP00000368031.3	16	MANE Select
NM_001170536.3	RefSeq	NP_001164007.1	15	Standard
NM_018188.5	RefSeq	NP_060658.3	16	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of cell growth
mitochondrion organization
negative regulation of apoptotic process

Molecular Function

ATP binding
zinc ion binding

Cellular Component

mitochondrion
mitochondrial inner membrane
integral component of membrane
mitochondrial nucleoid

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378755
Coding exons: 16
Length: 22537
Individuals with no LoFs: 125701
Homozygous LoFs: 0
Heterozygous LoFs: 41
Defined: 125742
p: 0.000163

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0126	401	402	0.998	0.0000293	4053
Missense (PolyPhen)		77	101.61	0.75776		1122
Synonymous	-0.993	188	171	1.10	0.0000126	1285
Loss of Function	2.35	19	33.7	0.564	0.00000194	368

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00019	0.00018	rare
Latino/Admixed American	0.00040	0.00038	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000047	0.000046	rare
European (Non-Finnish)	0.00015	0.00014	rare
South Asian	0.00013	0.00013	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Essential for mitochondrial network organization, mitochondrial metabolism and cell growth at organism and cellular level. May play an important role in mitochondrial protein synthesis. May also participate in mitochondrial DNA replication. May bind to mitochondrial DNA D-loops and contribute to nucleoid stability. Required for enhanced channeling of cholesterol for hormone-dependent steroidogenesis. {ECO:0000269|PubMed:17210950, ECO:0000269|PubMed:20154147, ECO:0000269|PubMed:22453275}.;
Disease: DISEASE: Harel-Yoon syndrome (HAYOS) [MIM:617183]: A syndrome characterized by global developmental delay, hypotonia, intellectual disability, and axonal neuropathy. Some patients have optic atrophy and hypertrophic cardiomyopathy. HAYOS inheritance can be autosomal dominant or autosomal recessive. {ECO:0000269|PubMed:27640307}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.0950
RVIS EVS: 0.12
RVIS percentile EVS: 62.21

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.735

Gene Damage Prediction

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