TNFRSF12A

Chr 16

TNF receptor superfamily member 12A

Also known as: CD266, FN14, TWEAKR

NCBI Gene: 51330 ENSG00000006327 UniProt: Q9NP84

The TNFRSF12A protein functions as a receptor for TNFSF12/TWEAK and regulates apoptosis, angiogenesis, endothelial cell proliferation, and wound healing. Mutations cause Opitz GBBB syndrome type 2, an X-linked disorder characterized by developmental abnormalities affecting multiple organ systems including craniofacial features, cardiac defects, and genitourinary anomalies. The gene shows tolerance to loss-of-function variants (pLI 0.018, LOEUF 1.53), suggesting haploinsufficiency may not be the primary disease mechanism.

ResearchSummary from RefSeq, UniProt

Involved in positive regulation of extrinsic apoptotic signaling pathway and regulation of wound healing. Predicted to be located in cell surface and ruffle. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2025]

ResearchGenerating clinical summary…

GOFmechanismLOEUF 1.53

Clinical Summary— TNFRSF12A

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

16 VUS of 22 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.53LOEUF

pLI 0.018

Z-score 0.78

OE 0.62 (0.28–1.53)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.14Z-score

OE missense 1.05 (0.85–1.30)

60 obs / 57.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.62 (0.28–1.53)

0≤0.351.4

Missense OE?1.05 (0.85–1.30)

0≤0.61.4

Synonymous OE?1.36

0≤1.21.6

LoF obs/exp: 3 / 4.8Missense obs/exp: 60 / 57.0Syn Z: -1.40

This gene — mechanism propensity

0.6065th %ile

GOF

0.7127th %ile

LOF

0.3357th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction 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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

22 submitted variants in ClinVar

ClinVar

Classification Summary

VUS16

Likely Benign1

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	16	0	16
Likely Benign	1	0	1
Benign	0	1	1
Total	17	1	18

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

View in ClinVar →

35 pathogenic / likely-pathogenic (of 44) ClinVar copy-number / structural variants overlap TNFRSF12A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →