FHL5

Chr 6AR

four and a half LIM domains 5

Also known as: 1700027G07Rik, ACT, FHL-5, dJ393D12.2

NCBI Gene: 9457 ENSG00000112214 UniProt: Q5TD97 OMIM: 613101

This gene encodes a protein that stimulates CREM transcriptional activity and may regulate spermatogenesis. Mutations cause autosomal recessive familial hemophagocytic lymphohistiocytosis type 5, which can occur with or without microvillus inclusion disease. The gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is coordinately expressed with activator of cAMP-responsive element modulator (CREM). It is associated with CREM and confers a powerful transcriptional activation function. CREM acts as a transcription factor essential for the differentiation of spermatids into mature spermatozoa. There are multiple polyadenylation sites found in this gene. Polymorphisms in this gene may be associated with susceptibility for migraine headaches. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Apr 2016]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Hemophagocytic lymphohistiocytosis, familial, 5, with or without microvillus inclusion diseaseMIM #613101

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Hemophagocytic lymphohistiocytosis, familial, 5, with or without microvillus inclusion disease; no ClinGen or GenCC tier

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

1.61

LOEUF

—

Mechanism

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.61LOEUF

pLI 0.000

Z-score -0.14

OE 1.04 (0.69–1.61)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.31Z-score

OE missense 1.07 (0.94–1.22)

161 obs / 150.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.04 (0.69–1.61)

0≤0.351.4

Missense OE?1.07 (0.94–1.22)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 14 / 13.4Missense obs/exp: 161 / 150.2Syn Z: 0.43

Background carrier burden — how many people carry a rare variant somewhere in FHL5?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 190

358 rare PASS variants

Rare truncating (LoF)

1 in 2,100

66 rare PASS variants

Rare synonymous (reference)

1 in 340

124 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FHL5. 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 320	1 in 3,300
South Asian	~43k	1 in 190	1 in 610
Remaining (unassigned)	~30k	1 in 190	1 in 2,200
European (Finnish)	~27k	1 in 810	≈ 1 in 27,000
Admixed American	~22k	1 in 260	1 in 1,700
African / African American	~21k	1 in 140	1 in 720
East Asian	~20k	1 in 200	1 in 2,200
Ashkenazi Jewish	~13k	1 in 500	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 220	≈ 1 in 960

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 5 coding exons well covered in gnomAD exomes and genomes.? see exons ↓