FHL3

Chr 1AR

four and a half LIM domains 3

Also known as: SLIM2

NCBI Gene: 2275ENSG00000183386UniProt: Q13643OMIM: 608898

The protein encoded by this gene is a member of a family of proteins containing a four-and-a-half LIM domain, which is a highly conserved double zinc finger motif. The encoded protein has been shown to interact with the cancer developmental regulators SMAD2, SMAD3, and SMAD4, the skeletal muscle myogenesis protein MyoD, and the high-affinity IgE beta chain regulator MZF-1. This protein may be involved in tumor suppression, repression of MyoD expression, and repression of IgE receptor expression. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

GeneReviewsOMIMResearchGenerating clinical summary…
MultiplemechanismARLOEUF 0.841 OMIM phenotype
Clinical Summary— FHL3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
42 VUS of 53 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
📖
GeneReview available — FHL3
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?
0.84LOEUF
pLI 0.002
Z-score 2.01
OE 0.45 (0.26–0.84)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?
0.79Z-score
OE missense 0.84 (0.73–0.95)
153 obs / 183.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.45 (0.26–0.84)
0≤0.351.4
Missense OE?0.84 (0.73–0.95)
0≤0.61.4
Synonymous OE?0.95
0≤1.21.6
LoF obs/exp: 7 / 15.6Missense obs/exp: 153 / 183.2Syn Z: 0.35

This gene — mechanism propensity

DN
0.6454th %ile
GOF
0.6737th %ile
LOF
0.3647th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

53 submitted variants in ClinVar

ClinVar

Classification Summary

VUS42
Likely Benign4
Benign1
42
VUS
4
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
0
0
0
Likely Pathogenic
0
0
0
0
0
VUS
0
42
0
0
42
Likely Benign
0
1
0
3
4
Benign
0
1
0
0
1
Total0440347

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

5 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap FHL3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

FHL3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients