TIAM1

Chr 21AR

TIAM Rac1 associated GEF 1

Also known as: NEDLDS, TIAM-1

This gene encodes a RAC1-specific guanine nucleotide exchange factor (GEF). GEFs mediate the exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP). The binding of GTP induces a conformational change in RAC1 that allows downstream effectors to bind and transduce a signal. This gene thus regulates RAC1 signaling pathways that affect cell shape, migration, adhesion, growth, survival, and polarity, as well as influencing actin cytoskeletal formation, endocytosis, and membrane trafficking. This gene thus plays an important role in cell invasion, metastasis, and carcinogenesis. In addition to RAC1, the encoded protein activates additional Rho-like GTPases such as CDC42, RAC2, RAC3 and RHOA. This gene encodes multiple protein isoforms that experience a diverse array of intramolecular, protein-protein, and phosphorylation interactions as well as phosphoinositide binding. Both the longer and shorter isoforms have C-terminal Dbl homology (DH) and pleckstrin homology (PH) domains while only the longer isoforms of this gene have the N-terminal myristoylation site and the downstream N-terminal PH domain, ras-binding domain (RBD), and PSD-95/DlgA/ZO-1 (PDZ) domain. [provided by RefSeq, Jul 2017]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with language delay and seizuresMIM #619908
AR
0
Active trials
38
Pathogenic / LP
366
ClinVar variants
23
Pubs (1 yr)
1.7
Missense Z
0.30
LOEUF· LoF intolerant
Clinical SummaryTIAM1
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.96). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
38 Pathogenic / Likely Pathogenic· 261 VUS of 366 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.30LOEUF
pLI 0.957
Z-score 6.48
OE 0.20 (0.130.30)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
1.70Z-score
OE missense 0.84 (0.800.90)
801 obs / 948.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.20 (0.130.30)
00.351.4
Missense OE0.84 (0.800.90)
00.61.4
Synonymous OE1.04
01.21.6
LoF obs/exp: 15 / 76.0Missense obs/exp: 801 / 948.1Syn Z: -0.60
LOF
DN
0.4289th %ile
GOF
0.5170th %ile
LOF
0.68top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.30

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

366 submitted variants in ClinVar

Classification Summary

Pathogenic37
Likely Pathogenic1
VUS261
Likely Benign50
Benign15
Conflicting2
37
Pathogenic
1
Likely Pathogenic
261
VUS
50
Likely Benign
15
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
4
33
0
37
Likely Pathogenic
0
1
0
0
1
VUS
2
244
15
0
261
Likely Benign
0
11
5
34
50
Benign
0
7
3
5
15
Conflicting
2
Total22675639366

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

View in ClinVar →

TIAM1 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence