FTH1

Chr 11AD

ferritin heavy chain 1

Also known as: FHC, FTH, FTHL6, HFE5, NBIA9, PIG15, PLIF

NCBI Gene: 2495 ENSG00000167996 UniProt: P02794 OMIM: 134770

The ferritin heavy chain stores iron in a soluble, non-toxic form and has ferroxidase activity that oxidizes ferrous iron to ferric iron for cellular iron homeostasis. Mutations cause neurodegeneration with brain iron accumulation 9 and hemochromatosis type 5, both involving abnormal iron metabolism affecting the brain and other organs. Inheritance is autosomal dominant.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the heavy subunit of ferritin, the major intracellular iron storage protein in prokaryotes and eukaryotes. It is composed of 24 subunits of the heavy and light ferritin chains. Variation in ferritin subunit composition may affect the rates of iron uptake and release in different tissues. A major function of ferritin is the storage of iron in a soluble and nontoxic state. Defects in ferritin proteins are associated with several neurodegenerative diseases. This gene has multiple pseudogenes. Several alternatively spliced transcript variants have been observed, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Hemochromatosis, type 5MIM #615517

Neurodegeneration with brain iron accumulation 9MIM #620669

UniProtHemochromatosis 5

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

749

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.78

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.78LOEUF

pLI 0.140

Z-score 2.05

OE 0.30 (0.14–0.78)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.86Z-score

OE missense 0.75 (0.62–0.91)

72 obs / 95.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.14–0.78)

0≤0.351.4

Missense OE?0.75 (0.62–0.91)

0≤0.61.4

Synonymous OE?1.17

0≤1.21.6

LoF obs/exp: 3 / 10.0Missense obs/exp: 72 / 95.8Syn Z: -0.88

Background carrier burden — how many people carry a rare variant somewhere in FTH1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 420

238 rare PASS variants

Rare truncating (LoF)

1 in 1,000

47 rare PASS variants

Rare synonymous (reference)

1 in 490

93 rare PASS variants

Rare missense and truncating variants are carried at similar rates in FTH1; this gene does not show strong loss-of-function constraint by this measure. 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 610	1 in 990
South Asian	~43k	1 in 250	1 in 1,200
Remaining (unassigned)	~30k	1 in 370	1 in 2,200
European (Finnish)	~27k	1 in 950	1 in 2,400
Admixed American	~22k	1 in 230	1 in 2,900
African / African American	~21k	1 in 260	1 in 2,900
East Asian	~20k	1 in 630	1 in 1,400
Ashkenazi Jewish	~13k	≈ 1 in 3,300	≈ 1 in 13,000
Middle Eastern	~2,884	≈ 1 in 690	≈ 1 in 580

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): All 4 coding exons well covered in gnomAD exomes and genomes.? see exons ↓