TIAM1

protein-coding

TIAM Rac1 associated GEF 1, the group of Dbl family Rho GEFs|PDZ domain containing|Pleckstrin homology domain containing

Gene summary

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]

MANE transcript

NM_001353694.2

Inheritance

ClinVar variants

P:6U:268B:70

Top phenotype

Neurodevelopmental disorder with language delay and seizures

gnomAD constraint

pLI —, LoF o/e 0.2

Max pathogenic AF

—

Genomic locus

chr21:31,118,416-31,559,977

External References & Databases

Ensembl (ENSG00000156299)

Transcript & Mutation Effects

hg38 • Region Span ~441.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with language delay and seizuresLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0859256

Submitter: Ambry Genetics

neurodevelopmental disorder with language delay and seizuresSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859256

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorder with language delay and seizuresSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0859256

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with language delay and seizuresAR

Manifestation: Craniofacial; Endocrine; Neurologic

Intervention: Endocrine

Rationale: Among other findings, individuals have been described with endocrine disorders such as hypothyroidism, and awareness may allow medical management

Refs: 35240055

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TIAM1 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 237

not providedTotal: 85

TIAM1-related disorderTotal: 59

Neurodevelopmental disorder with language delay and seizuresTotal: 16

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001353694.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	46 clinvar	4 clinvar	52
missense	4 clinvar	2 clinvar	259 clinvar	15 clinvar	5 clinvar	285
nonsense			2 clinvar			2
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	4	2	268	61	9	344

Highest pathogenic variant AF is 0.00059348246

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 44 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001353694.2	RefSeq	NP_001340623.1	25	MANE Select
ENST00000541036.6	Ensembl	ENSP00000441570.2	25	MANE Select
NM_001353684.2	RefSeq	NP_001340613.1	13	Standard
NM_001353685.2	RefSeq	NP_001340614.1	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tight junction - Homo sapiens (human)
Chemokine signaling pathway - Homo sapiens (human)
Regulation of actin cytoskeleton - Homo sapiens (human)
cAMP signaling pathway - Homo sapiens (human)
Rap1 signaling pathway - Homo sapiens (human)

Biological Process

cardiac muscle hypertrophy
apoptotic process
cell-matrix adhesion
G protein-coupled receptor signaling pathway
positive regulation of cell population proliferation

Molecular Function

guanyl-nucleotide exchange factor activity
Rho guanyl-nucleotide exchange factor activity
protein binding
microtubule binding
lipid binding

Cellular Component

nucleus
cytosol
microtubule
plasma membrane
cell-cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000286827
Coding exons: 25
Length: 441557
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 34
Defined: 125748
p: 0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.70	801	948	0.845	0.0000591	10487
Missense (PolyPhen)		179	250.82	0.71365		2785
Synonymous	-0.595	417	402	1.04	0.0000287	3120
Loss of Function	6.48	15	76.0	0.197	0.00000426	838

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000055	0.000054	rare
Finnish	0.00032	0.00032	rare
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.000098	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Modulates the activity of RHO-like proteins and connects extracellular signals to cytoskeletal activities. Acts as a GDP- dissociation stimulator protein that stimulates the GDP-GTP exchange activity of RHO-like GTPases and activates them. Activates RAC1, CDC42, and to a lesser extent RHOA. Required for normal cell adhesion and cell migration. {ECO:0000269|PubMed:20361982}.;

Recessive Scores

pRec: 0.333

Intolerance Scores

LoFtool: 0.421
RVIS EVS: -0.91
RVIS percentile EVS: 9.84

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.737

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	Medium	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High