FERMT3

Chr 11AR

FERM domain containing kindlin 3

Also known as: KIND3, MIG-2, MIG2B, UNC112C, URP2, URP2SF

NCBI Gene: 83706 ENSG00000149781 UniProt: Q86UX7 OMIM: 607901

The FERMT3 protein activates integrins in hematopoietic cells and is required for integrin-mediated platelet adhesion and leukocyte adhesion to endothelial cells. Mutations cause autosomal recessive leukocyte adhesion deficiency type III (LAD-III), which affects both immune function and hemostasis. The gene is not highly constrained against loss-of-function variants.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Kindlins are a small family of proteins that mediate protein-protein interactions involved in integrin activation and thereby have a role in cell adhesion, migration, differentiation, and proliferation. The protein encoded by this gene has a key role in the regulation of hemostasis and thrombosis. This protein may also help maintain the membrane skeleton of erythrocytes. Mutations in this gene cause the autosomal recessive leukocyte adhesion deficiency syndrome-III (LAD-III). Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2010]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.561 OMIM phenotype

Clinical Summary— FERMT3

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Gene-Disease Validity (ClinGen)

leukocyte adhesion deficiency 3 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

14 unique Pathogenic / Likely Pathogenic· 160 VUS of 392 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.56LOEUF

pLI 0.000

Z-score 3.64

OE 0.35 (0.23–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.51Z-score

OE missense 0.79 (0.72–0.87)

332 obs / 418.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.35 (0.23–0.56)

0≤0.351.4

Missense OE?0.79 (0.72–0.87)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 13 / 36.8Missense obs/exp: 332 / 418.8Syn Z: -0.26

This gene — mechanism propensity

0.6162th %ile

GOF

0.6345th %ile

LOF

0.3649th %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

392 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic5

VUS160

Likely Benign204

Benign8

Pathogenic

Likely Pathogenic

160

VUS

204

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	0	0	0	9
Likely Pathogenic	5	0	0	0	5
VUS	3	150	7	0	160
Likely Benign	0	3	84	117	204
Benign	0	0	7	1	8
Total	17	153	98	118	386

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

View in ClinVar →

5 pathogenic / likely-pathogenic (of 8) ClinVar copy-number / structural variants overlap FERMT3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →