TTI2

protein-coding

TELO2 interacting protein 2, the group of Armadillo like helical domain containing|TTT complex

Gene summary

This gene encodes a regulator of the DNA damage response. The protein is a component of the Triple T complex (TTT) which also includes telomere length regulation protein and TELO2 interacting protein 1. The TTT complex is involved in cellular resistance to DNA damage stresses and may act as a regulator of phosphoinositide-3-kinase-related protein kinase (PIKK) abundance. [provided by RefSeq, May 2013]

Previous symbols:

C8orf41

MANE transcript

NM_001102401.4

Inheritance

ClinVar variants

P:11U:83B:41

Top phenotype

Intellectual developmental disorder, autosomal recessive 39

gnomAD constraint

pLI —, LoF o/e 0.66

Max pathogenic AF

—

Genomic locus

chr8:33,473,386-33,513,185

External References & Databases

Ensembl (ENSG00000129696)

Transcript & Mutation Effects

hg38 • Region Span ~39.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 39MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014238

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal recessive 39STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014238

Submitter: G2P

intellectual developmental disorder, autosomal recessive 39STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014238

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal recessive 39SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014238

Submitter: Orphanet

intellectual developmental disorder, autosomal recessive 39STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014238

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 39AR

Manifestation: Craniofacial; Dental; Musculoskeletal; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 21937992; 23956177

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TTI2 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 70

not providedTotal: 45

Severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndromeTotal: 20

not specifiedTotal: 17

TTI2-related disorderTotal: 8

MicrocephalyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001102401.4. 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	21 clinvar	1 clinvar	24
missense	5 clinvar		75 clinvar	17 clinvar	1 clinvar	98
nonsense		1 clinvar	2 clinvar			3
start loss						0
frameshift	2 clinvar	1 clinvar	2 clinvar			5
splice donor/acceptor (+/-2bp)		2 clinvar	2 clinvar		1 clinvar	5
Total	7	4	83	38	3	135

Highest pathogenic variant AF is 0.000047091133

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001102401.4	RefSeq	NP_001095871.1	7	MANE Select
ENST00000431156.7	Ensembl	ENSP00000411169.3	7	MANE Select
NM_001265581.2	RefSeq	NP_001252510.1	7	Standard
NM_001330505.3	RefSeq	NP_001317434.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Cellular Component

nucleoplasm
centrosome
cytosol
ASTRA complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000431156
Coding exons: 7
Length: 40216
Individuals with no LoFs: 125684
Homozygous LoFs: 0
Heterozygous LoFs: 64
Defined: 125748
p: 0.000255

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.289	284	271	1.05	0.0000142	3243
Missense (PolyPhen)		82	87.798	0.93396		1103
Synonymous	-0.296	118	114	1.04	0.00000604	1081
Loss of Function	1.41	13	19.8	0.657	9.47e-7	249

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00074	0.00074	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00027	0.00027	rare
South Asian	0.00013	0.00013	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulator of the DNA damage response (DDR). Part of the TTT complex that is required to stabilize protein levels of the phosphatidylinositol 3-kinase-related protein kinase (PIKK) family proteins. The TTT complex is involved in the cellular resistance to DNA damage stresses, like ionizing radiation (IR), ultraviolet (UV) and mitomycin C (MMC). Together with the TTT complex and HSP90 may participate in the proper folding of newly synthesized PIKKs. {ECO:0000269|PubMed:20801936, ECO:0000269|PubMed:20810650}.;
Disease: DISEASE: Mental retardation, autosomal recessive 39 (MRT39) [MIM:615541]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT39 affected individuals show delayed psychomotor development, severe speech delay, short stature, kyphoscoliosis, and dysmorphic facial features. Behavioral abnormalities include hyperactivity, aggression, and stereotypic movements. {ECO:0000269|PubMed:23956177}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0894

Intolerance Scores

RVIS EVS: 0.18
RVIS percentile EVS: 66.07

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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