ATAD3A

Chr 1ADAR

ATPase family AAA domain containing 3A

Also known as: HAYOS, PHRINL

NCBI Gene: 55210 ENSG00000197785 UniProt: Q9NVI7 OMIM: 612316

ATAD3A encodes a mitochondrial membrane protein essential for mitochondrial network organization, metabolism, protein synthesis, and cholesterol metabolism. Mutations cause Harel-Yoon syndrome and a neonatal lethal form of pontocerebellar hypoplasia with hypotonia and respiratory insufficiency, following both autosomal dominant and autosomal recessive inheritance patterns. The gene is extremely intolerant to loss-of-function variants, consistent with the severe neonatal phenotypes observed.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Harel-Yoon syndromeMIM #617183

ADAR

Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethalMIM #618810

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Harel-Yoon syndrome; Pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal; no ClinGen or GenCC tier

Interpreting a novel variant

The dominant disease is caused by dominant-negative changes and the recessive disease by loss of function (Gene2Phenotype). A single heterozygous truncating variant therefore fits the recessive disease and does not by itself explain a dominant presentation; a novel missense has to be read against the dominant mechanism.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

—

LOEUF

Multiple*

Mechanism· G2P

Some data sources returned errors (1)

gnomad: Error: gnomAD API error: 400

Population Genetics & Constraint

gnomAD

Constraint data not available from gnomAD.

Background carrier burden — how many people carry a rare variant somewhere in ATAD3A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 30

874 rare PASS variants

Rare truncating (LoF)

1 in 890

100 rare PASS variants

Rare synonymous (reference)

1 in 44

377 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ATAD3A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 37	1 in 640
South Asian	~43k	1 in 32	1 in 1,300
Remaining (unassigned)	~30k	1 in 31	1 in 1,200
European (Finnish)	~27k	1 in 130	1 in 2,400
Admixed American	~22k	1 in 30	1 in 1,000
African / African American	~21k	1 in 32	1 in 810
East Asian	~20k	1 in 37	1 in 820
Ashkenazi Jewish	~13k	1 in 180	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 35	≈ 1 in 2,800

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 16 coding exons well covered in gnomAD exomes; exons 1, 4 marginal. Genomes: 12 of 16 (exons 1, 3, 4, 11 below).? see exons ↓