TRAF7

Chr 16AD

TNF receptor associated factor 7

Also known as: CAFDADD, RFWD1, RNF119

NCBI Gene: 84231 ENSG00000131653 UniProt: Q6Q0C0 OMIM: 606692

TRAF7 encodes an E3 ubiquitin and SUMO-protein ligase that regulates innate immunity, inflammation, and apoptosis through protein modification and degradation pathways. Autosomal dominant mutations cause cardiac, facial, and digital anomalies with developmental delay, representing a recognizable multiple congenital anomaly syndrome. This condition affects multiple organ systems with congenital malformations apparent from birth.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.461 OMIM phenotype

Clinical Summary— TRAF7

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Gene-Disease Validity (ClinGen)

syndromic complex neurodevelopmental disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.28) despite low pLI — interpret in context.

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ClinVar Variants

21 unique Pathogenic / Likely Pathogenic· 133 VUS of 256 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.46LOEUF

pLI 0.022

Z-score 4.24

OE 0.28 (0.17–0.46)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.26Z-score

OE missense 0.56 (0.51–0.63)

248 obs / 440.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.28 (0.17–0.46)

0≤0.351.4

Missense OE?0.56 (0.51–0.63)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

LoF obs/exp: 11 / 39.9Missense obs/exp: 248 / 440.6Syn Z: -1.53

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongTRAF7-related developmental delay congenital anomalies and dysmorphic featuresOTHERAD

This gene — mechanism propensity

0.6840th %ile

GOF

0.6443th %ile

LOF

0.4136th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation · 95% of P/LP are missense

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

GOFThe second group included eight (31%) BAP1-wild-type tumors: two with TP53 mutations, one with a TRAF7 activating mutation, one with a SUZ12 inactivating mutation, and three with ALK rearrangements that we previously published.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 32504035 ↗

ClinVar Variant Classifications

256 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic14

VUS133

Likely Benign53

Benign10

Conflicting6

Pathogenic

Likely Pathogenic

133

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	7	0	0	7
Likely Pathogenic	0	13	1	0	14
VUS	14	115	4	0	133
Likely Benign	0	16	7	30	53
Benign	0	1	4	5	10
Conflicting	—				6
Total	14	152	16	35	223

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

36 pathogenic / likely-pathogenic (of 53) ClinVar copy-number / structural variants overlap TRAF7 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →