TRAF7

protein-coding

TNF receptor associated factor 7, the group of TNF receptor associated factors|Ring finger proteins|Zinc fingers TRAF-type|WD repeat domain containing

Gene summary

Tumor necrosis factor (TNF; see MIM 191160) receptor-associated factors, such as TRAF7, are signal transducers for members of the TNF receptor superfamily (see MIM 191190). TRAFs are composed of an N-terminal cysteine/histidine-rich region containing zinc RING and/or zinc finger motifs; a coiled-coil (leucine zipper) motif; and a homologous region that defines the TRAF family, the TRAF domain, which is involved in self-association and receptor binding.[supplied by OMIM, Apr 2004]

Previous symbols:

RFWD1

MANE transcript

NM_032271.3

Inheritance

ClinVar variants

P:27U:170B:67

Top phenotype

Cardiac, facial, and digital anomalies with developmental delay

gnomAD constraint

pLI —, LoF o/e 0.28

Max pathogenic AF

—

Genomic locus

chr16:2,155,698-2,178,129

External References & Databases

Ensembl (ENSG00000131653)

Transcript & Mutation Effects

hg38 • Region Span ~22.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cardiac, facial, and digital anomalies with developmental delaySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032572

Submitter: G2P

cardiac, facial, and digital anomalies with developmental delayDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032572

Submitter: Ambry Genetics

cardiac, facial, and digital anomalies with developmental delaySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032572

Submitter: Labcorp Genetics (formerly Invitae)

cardiac, facial, and digital anomalies with developmental delaySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032572

Submitter: PanelApp Australia

cardiac, facial, and digital anomalies with developmental delayDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0032572

Submitter: Illumina

syndromic complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800439

Submitter: ClinGen

TRAF7 is a known mediator of the MAPK and NFKB signaling pathways and is involved in multiple biologic processes, such as ubiquitination. *TRAF7* was first reported in relation to autosomal dominant syndromic complex neurodevelopmental disorder in 2018 (Tokita et al., PMID: 29961569). This is a multisystemic developmental disorder with developmental delay/intellectual disability, variable cardiac and digital anomalies, and recognizable facial features. Some patients may have autism spectrum disorder, seizures, hearing loss or ocular abnormalities. Thirteen *de novo* missense variants that have been reported in 16 probands in 2 publications (PMIDs: 29961569, 32376980) are included in this curation. More genetic evidence is available in the literature (PMIDs: 34513876, 37067385, 38569228, 38612512) but the maximum score for genetic evidence (12 points) has been reached. Several variants are recurrent (including p.Arg655Gln and p.Phe617Leu), and most cluster within the WD40 repeats of the TRAF7 protein, suggesting dominant-negative and/or gain-of-function effects. This gene-disease relationship is also supported by zebrafish and xenopus *traf7* model systems (PMID: 37043537), and functional studies demonstrating transcriptional changes and altered ERK signaling in the presence of pathogenic *TRAF7* variants (PMID: 29961569, 32376980). In summary, there is definitive evidence supporting the relationship between *TRAF7* and autosomal dominant syndromic complex neurodevelopmental disorder. 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 Intellectual Disability and Autism Gene Curation Expert Panels on the meeting date September 6, 2023 (SOP Version 9).

Clinical Genomic Database (CGD)

Cardiac, facial, and digital anomalies with developmental delayAD

Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Cardiovascular

Rationale: Among other findings, individuals have been described with heart anomalies (eg, including structural anomalies and arrthymia), and awareness may allow prompt diagnosis and management

Refs: 25961944; 29961569

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TRAF7 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 114

Inborn genetic diseasesTotal: 67

Cardiac, facial, and digital anomalies with developmental delayTotal: 48

TRAF7-related disorderTotal: 46

not specifiedTotal: 35

TRAF7-associated heart defect-digital anomalies-facial dysmorphism-motor and speech delay syndromeTotal: 2

Cone-rod synaptic disorder syndrome, congenital nonprogressiveTotal: 1

Global developmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032271.3. 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	44 clinvar	3 clinvar	50
missense	7 clinvar	20 clinvar	144 clinvar	19 clinvar	1 clinvar	191
nonsense			4 clinvar			4
start loss			1 clinvar			1
frameshift			5 clinvar			5
splice donor/acceptor (+/-2bp)			13 clinvar			13
Total	7	20	170	63	4	264

Highest pathogenic variant AF is 6.8561997e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 71 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032271.3	RefSeq	NP_115647.2	20	MANE Select
ENST00000326181.11	Ensembl	ENSP00000318944.6	20	MANE Select
ENST00000564067.5	Ensembl	ENSP00000457735.1	3	Standard
ENST00000565383.5	Ensembl	ENSP00000479297.1	3	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Immune System
Adaptive Immune System
Antigen processing: Ubiquitination & Proteasome degradation
Class I MHC mediated antigen processing & presentation
TNFalpha

Biological Process

ribosomal large subunit assembly
activation of MAPKKK activity
apoptotic process
Notch signaling pathway
protein ubiquitination

Molecular Function

ubiquitin-protein transferase activity
protein binding
zinc ion binding

Cellular Component

ubiquitin ligase complex
nucleolus
plasma membrane
cytoplasmic vesicle
intracellular membrane-bounded organelle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000326181
Coding exons: 20
Length: 22432
Individuals with no LoFs: 125719
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125742
p: 0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.26	248	441	0.563	0.0000289	4385
Missense (PolyPhen)		40	130.65	0.30616		1396
Synonymous	-1.53	215	188	1.14	0.0000140	1281
Loss of Function	4.24	11	39.9	0.276	0.00000197	432

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000063	0.000062	rare
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.000099	0.000097	rare
South Asian	0.000098	0.000098	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin ligase capable of auto-ubiquitination, following phosphorylation by MAP3K3. Potentiates MEKK3-mediated activation of the NF-kappa-B, JUN/AP1 and DDIT3 transcriptional regulators. Induces apoptosis when overexpressed. {ECO:0000269|PubMed:14743216, ECO:0000269|PubMed:15001576}.;

Recessive Scores

pRec: 0.141

Intolerance Scores

LoFtool: 0.468
RVIS EVS: -1.51
RVIS percentile EVS: 3.5

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.961

Gene Damage Prediction

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