FASTKD3

Chr 5

FASTK mitochondrial RNA regulator 3

NCBI Gene: 79072 ENSG00000124279 UniProt: Q14CZ7 OMIM: 617530

The protein regulates mitochondrial mRNA stability and translation, specifically increasing steady-state levels of several mitochondrial transcripts and promoting complex IV assembly and activity for normal mitochondrial respiration. Mutations cause autosomal recessive mitochondrial encephalomyopathy with seizures and hearing loss, typically presenting in infancy with neurological and cardiac manifestations. The gene is highly intolerant to loss-of-function variants, reflecting its essential role in mitochondrial function.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of a small family of Fas-activated serine/threonine kinase domain (FASTKD) containing proteins that share an amino terminal mitochondrial targeting domain and multiple carboxy terminal FAST domains as well as a putative RNA-binding RAP domain. The members of this family are ubiquitously expressed and are generally most abundant in mitochondria-enriched tissues such as heart, skeletal muscle and brown-adipose tissue. Some members of this protein family may play a role in apoptosis. The protein encoded by this gene interacts with components of the mitochondrial respiratory and translation networks. A pseudogene of this gene is also present on chromosome 5. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2013]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.15

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.15LOEUF

pLI 0.000

Z-score 1.01

OE 0.77 (0.53–1.15)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.81Z-score

OE missense 0.88 (0.80–0.96)

296 obs / 338.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.77 (0.53–1.15)

0≤0.351.4

Missense OE?0.88 (0.80–0.96)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 17 / 22.1Missense obs/exp: 296 / 338.1Syn Z: -0.12

Background carrier burden — how many people carry a rare variant somewhere in FASTKD3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 95

790 rare PASS variants

Rare truncating (LoF)

1 in 670

148 rare PASS variants

Rare synonymous (reference)

1 in 200

300 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FASTKD3. 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 180	1 in 630
South Asian	~43k	1 in 82	1 in 670
Remaining (unassigned)	~30k	1 in 72	1 in 860
European (Finnish)	~27k	1 in 450	1 in 1,400
Admixed American	~22k	1 in 110	1 in 730
African / African American	~21k	1 in 97	1 in 610
East Asian	~20k	1 in 66	1 in 2,200
Ashkenazi Jewish	~13k	1 in 820	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 90	1 in 410

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): 4 of 6 coding exons well covered in gnomAD exomes; exons 6, 7 marginal. Genomes: all 6.? see exons ↓