TRAPPC9

protein-coding

trafficking protein particle complex subunit 9, the group of Trafficking protein particle complex subunits

Gene summary

This gene encodes a protein that likely plays a role in NF-kappa-B signaling. Mutations in this gene have been associated with autosomal-recessive cognitive disability. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]

MANE transcript

NM_001160372.4

Inheritance

ClinVar variants

P:78U:371B:285

Top phenotype

Intellectual developmental disorder, autosomal recessive 13

gnomAD constraint

pLI —, LoF o/e 0.55

Max pathogenic AF

—

Genomic locus

chr8:139,727,725-140,458,579

External References & Databases

Ensembl (ENSG00000167632)

Transcript & Mutation Effects

hg38 • Region Span ~730.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, autosomal recessive 13DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013173

Submitter: G2P

intellectual disability-obesity-brain malformations-facial dysmorphism syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018123

Submitter: Orphanet

intellectual developmental disorder, autosomal recessive 13STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013173

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal recessive 13MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013173

Submitter: Ambry Genetics

intellectual disability-obesity-brain malformations-facial dysmorphism syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018123

Submitter: ClinGen

Variants in the TRAPPC9 gene have been reported in multiple individuals with intellectual disability-obesity-brain malformations-facial dysmorphism syndrome since 2009 (Mir et al. 2009). More than 10 unique variants predicted to cause a loss of function of the protein have been described. In addition to SNVs and indels, intragenic CNVs have also been identified in affected individuals (Koifman et al. 2010, Mortreux et al. 2018). While all reported variants are likely gene disrupting, there is a single report of a homozygous missense variant in 2 siblings with severe ID, microcephaly and hypoplasia of the corpus callosum (Duerinckx et al. 2018). Since this is the only family with a missense variant described, further reports are needed to confirm the contribution of bi-allelic missense variants to TRAPPC9-related disorders. In summary, TRAPPC9 is definitively associated with intellectual disability-obesity-brain malformations-facial dysmorphism syndrome.

intellectual developmental disorder, autosomal recessive 13STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013173

Submitter: PanelApp Australia

autosomal recessive non-syndromic intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019502

Submitter: Orphanet

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 13AR

Manifestation: Craniofacial; Endocrine; 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: 17120046; 20004765; 20004763; 20004764; 21629298; 22549410; 22989526

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRAPPC9 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 716

Inborn genetic diseasesTotal: 276

not specifiedTotal: 118

Intellectual disability, autosomal recessive 13Total: 112

TRAPPC9-related disorderTotal: 56

Intellectual disabilityTotal: 9

Abnormality of the nervous systemTotal: 3

Intellectual disability-obesity-brain malformations-facial dysmorphism syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001160372.4. 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			10 clinvar	255 clinvar	2 clinvar	267
missense		3 clinvar	349 clinvar	28 clinvar		380
nonsense	18 clinvar	9 clinvar	3 clinvar			30
start loss						0
frameshift	20 clinvar	11 clinvar	4 clinvar			35
splice donor/acceptor (+/-2bp)	4 clinvar	13 clinvar	5 clinvar			22
Total	42	36	371	283	2	734

Highest pathogenic variant AF is 0.000050188733

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 64 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001160372.4	RefSeq	NP_001153844.1	22	MANE Select
ENST00000438773.4	Ensembl	ENSP00000405060.3	22	MANE Select
NM_001321646.2	RefSeq	NP_001308575.1	21	Standard
NM_001374682.1	RefSeq	NP_001361611.1	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Vesicle-mediated transport
Membrane Trafficking
Post-translational protein modification
Metabolism of proteins
Transport to the Golgi and subsequent modification

Biological Process

cerebral cortex development
neuron differentiation
COPII vesicle coating
positive regulation of NF-kappaB transcription factor activity

Molecular Function

protein binding
Rab guanyl-nucleotide exchange factor activity

Cellular Component

Golgi membrane
endoplasmic reticulum
trans-Golgi network
cytosol
TRAPP complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000389328
Coding exons: 23
Length: 726093
Individuals with no LoFs: 125646
Homozygous LoFs: 0
Heterozygous LoFs: 102
Defined: 125748
p: 0.000406

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.48	626	739	0.847	0.0000489	8073
Missense (PolyPhen)		331	398.34	0.83096		4318
Synonymous	-1.64	353	316	1.12	0.0000231	2503
Loss of Function	3.23	32	58.7	0.545	0.00000318	650

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00039	0.00037	rare
Latino/Admixed American	0.0010	0.0010	notable
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00028	0.00027	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00038	0.00038	rare
South Asian	0.00020	0.00020	rare
Other	0.00067	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions as an activator of NF-kappa-B through increased phosphorylation of the IKK complex. May function in neuronal cells differentiation. May play a role in vesicular transport from endoplasmic reticulum to Golgi. {ECO:0000269|PubMed:15951441}.;

Intolerance Scores

LoFtool: 0.0201
RVIS EVS: -1.65
RVIS percentile EVS: 2.77

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.380

Gene Damage Prediction

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