LRRFIP2

Chr 3

LRR binding FLII interacting protein 2

Also known as: HUFI-2

NCBI Gene: 9209 ENSG00000093167 UniProt: Q9Y608

The protein encoded by LRRFIP2 activates nuclear factor kappa B signaling by binding to toll-like receptor 4 and modulates the NLRP3 inflammasome through recruitment of caspase-1 inhibitors. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in infancy, characterized by severe intellectual disability, refractory seizures, and progressive brain atrophy. This gene is not highly constrained against loss-of-function variants.

GeneReviews ResearchSummary from RefSeq, UniProt

The protein encoded by this gene, along with MYD88, binds to the cytosolic tail of toll-like receptor 4 (TLR4), which results in activation of nuclear factor kappa B signaling. The ubiquitin-like protein FAT10 prevents the interaction of the encoded protein and TLR4, thereby inactivating the nuclear factor kappa B signaling pathway. In addition, this protein can downregulate the NLRP3 inflammasome by recruiting the caspase-1 inhibitor Flightless-I to the inflammasome complex. [provided by RefSeq, Jan 2017]

GeneReviews ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.98

LOEUF

Mechanism· predicted

📖

GeneReview available — LRRFIP2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.98LOEUF

pLI 0.000

Z-score 1.66

OE 0.77 (0.61–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.71Z-score

OE missense 0.90 (0.82–0.98)

348 obs / 387.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.77 (0.61–0.98)

0≤0.351.4

Missense OE?0.90 (0.82–0.98)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 46 / 59.8Missense obs/exp: 348 / 387.5Syn Z: 0.96

Background carrier burden — how many people carry a rare variant somewhere in LRRFIP2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 52

919 rare PASS variants

Rare truncating (LoF)

1 in 700

194 rare PASS variants

Rare synonymous (reference)

1 in 210

313 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for LRRFIP2. 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 72	1 in 770
South Asian	~43k	1 in 62	1 in 600
Remaining (unassigned)	~30k	1 in 63	1 in 690
European (Finnish)	~27k	1 in 280	1 in 2,200
Admixed American	~22k	1 in 58	1 in 410
African / African American	~21k	1 in 71	1 in 460
East Asian	~20k	1 in 55	1 in 410
Ashkenazi Jewish	~13k	1 in 290	1 in 1,400
Middle Eastern	~2,884	1 in 54	1 in 410

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 22 of 27 coding exons well covered in gnomAD exomes; exons 7, 8, 16, 26, 28 marginal. Genomes: all 27.? see exons ↓