TTC7A

protein-coding

tetratricopeptide repeat domain 7A, the group of Tetratricopeptide repeat domain containing|PI4KA lipid kinase complex

Gene summary

This gene encodes a protein containing tetratricopeptide repeats. Mutations in this gene disrupt intestinal development and can cause early onset inflammatory bowel disease and intestinal atresia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2014]

Previous symbols:

TTC7

MANE transcript

NM_020458.4

Inheritance

ClinVar variants

P:91U:465B:318

Top phenotype

Gastrointestinal defects and immunodeficiency syndrome 1

gnomAD constraint

pLI —, LoF o/e 1.01

Max pathogenic AF

—

Genomic locus

chr2:46,915,869-47,076,137

External References & Databases

Ensembl (ENSG00000068724)

Transcript & Mutation Effects

hg38 • Region Span ~160.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

gastrointestinal defects and immunodeficiency syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0800030

Submitter: PanelApp Australia

multiple intestinal atresiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009465

Submitter: Orphanet

multiple intestinal atresiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009465

Submitter: ClinGen

TTC7A was first reported in relation to autosomal recessive congenital combined immunodeficiency and multiple intestinal atresia (CID-MIA) (PMID: 23423984). TTC7A deficiency is associated with an immunodeficiency primarily characterized by T and B cell lymphopenia, very low immunoglobulin levels and variable numbers of intestinal atresias effecting the small and/or large bowel. The reported severity of immunodeficiency is variable and is likely due to the residual activity of TTC7A protein product. There have also been reports of TTC7A variants associated with very early onset inflammatory bowel disease. Over 52 variants have been reported and are predominantly composed of frameshift indels, nonsense and variants in splice sites resulting in loss of exons. Evidence supporting this gene-disease relationship includes case-level and experimental data. 21 unique variants from 15 probands across 5 publications were curated (PMID:23830146, 25174867, 29174094, 23423984, 24292712). Heterozygous carriers have not been shown to have a clinical phenotype. More evidence is available in the literature, but the maximum score for genetic evidence has been reached (12 pts). Experimentally, in vitro studies primarily use patient derived cells to support this gene-disease relationship for the immunodeficiency component of CID-MIA. Many of the published studies perform mechanistic analysis on enterocytes and are not reviewed here. Pertaining to the immune phenotype of CID-MIA, the TTC7A protein has been shown to be expressed in thymic tissue and lymphoblasts derived from patients (PMID: 23820146, 25174867). As well, functional data has demonstrated T cell from affected patients show impaired proliferation, cytoskeletal defects and increased activation induced cell death (PMID: 25174867, 25745186, 30455981). Mouse models of TTC7A deficiency replicate decreased thymus size and lymphocytopenia, do not phenocopy atresias seen in humans, and show alterations in iron metabolism not noted in human studies (PMID: 7579418, 16093647). This may imply differences in functionality between mouse and human orthologs. Mechanistically, TTC7A has been implicated in cytoskeletal dynamics, generation of phosphatidylinositol 4-phosphate on the inner plasma membrane, as well as regulator of chromatin structure and nuclear organization. However, there is no consensus as to how TTC7A causes immunodeficiency seen in CID-MIA patients. In summary, TTC7A is strongly associated with CID-MIA. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID-CID Working Group on 8/19/2021 (SOP Version 8).

multiple intestinal atresiaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009465

Submitter: Orphanet

multiple intestinal atresiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009465

Submitter: Ambry Genetics

gastrointestinal defects and immunodeficiency syndrome 1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0800030

Submitter: Labcorp Genetics (formerly Invitae)

gastrointestinal defects and immunodeficiency syndrome 1DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0800030

Submitter: G2P

Clinical Genomic Database (CGD)

Gastrointestinal defects and immunodeficiency syndrome 1AR

Manifestation: Allergy/Immunology/Infectious; Dermatologic; Gastrointestinal

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

Comments: HSCT has been described

Refs: 23423984; 25174867

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TTC7A variants in ClinVar

11 Conditions Cataloged

Multiple gastrointestinal atresiasTotal: 973

Inborn genetic diseasesTotal: 190

not providedTotal: 119

Gastrointestinal defects and immunodeficiency syndrome 1Total: 63

TTC7A-related disorderTotal: 37

not specifiedTotal: 24

Gastrointestinal defect and immunodeficiency syndromeTotal: 8

See casesTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020458.4. 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			3 clinvar	270 clinvar	10 clinvar	283
missense		11 clinvar	449 clinvar	34 clinvar	4 clinvar	498
nonsense	20 clinvar	11 clinvar	1 clinvar			32
start loss			1 clinvar			1
frameshift	18 clinvar	14 clinvar	1 clinvar			33
splice donor/acceptor (+/-2bp)	4 clinvar	13 clinvar	10 clinvar			27
Total	42	49	465	304	14	874

Highest pathogenic variant AF is 0.00005390321

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 62 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020458.4	RefSeq	NP_065191.2	20	MANE Select
ENST00000319190.11	Ensembl	ENSP00000316699.5	20	MANE Select
NM_001288951.2	RefSeq	NP_001275880.1	21	Standard
NM_001288953.2	RefSeq	NP_001275882.1	20	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cellular iron ion homeostasis
hemopoiesis
phosphatidylinositol phosphorylation
protein localization to plasma membrane

Cellular Component

cytoplasm
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000319190
Coding exons: 20
Length: 159981
Individuals with no LoFs: 125638
Homozygous LoFs: 0
Heterozygous LoFs: 110
Defined: 125748
p: 0.000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.775	570	520	1.10	0.0000314	5553
Missense (PolyPhen)		150	149.69	1.0021		1578
Synonymous	-0.0844	231	229	1.01	0.0000146	1706
Loss of Function	-0.0466	47	46.7	1.01	0.00000230	516

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00043	0.00043	rare
Latino/Admixed American	0.00058	0.00058	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00051	0.00049	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00051	0.00051	rare
South Asian	0.00027	0.00026	rare
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane (PubMed:23229899, PubMed:24417819). The complex acts as a regulator of phosphatidylinositol 4-phosphate (PtdIns(4)P) synthesis (Probable). In the complex, plays a central role in bridging PI4KA to EFR3B and FAM126A, via direct interactions (By similarity). {ECO:0000250|UniProtKB:Q86TV6, ECO:0000269|PubMed:23229899, ECO:0000269|PubMed:24417819}.;

Recessive Scores

pRec: 0.100

Intolerance Scores

LoFtool: 0.832
RVIS EVS: 0.01
RVIS percentile EVS: 54.18

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.256

Gene Damage Prediction

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