TNFRSF12A

Chr 16

TNF receptor superfamily member 12A

ENSG00000006327 UniProt: Q9NP84 OMIM: 605914

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.

OMIM ResearchSummary from RefSeq, UniProt

Receptor for TNFSF12/TWEAK. Weak inducer of apoptosis in some cell types. Promotes angiogenesis and the proliferation of endothelial cells. May modulate cellular adhesion to matrix proteins

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.53

LOEUF

GOF

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

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

Background carrier burden — how many people carry a rare variant somewhere in TNFRSF12A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 91

437 rare PASS variants

Rare truncating (LoF)

1 in 660

71 rare PASS variants

Rare synonymous (reference)

1 in 430

121 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TNFRSF12A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 110	1 in 830
South Asian	~43k	1 in 150	1 in 610
Remaining (unassigned)	~30k	1 in 91	1 in 510
European (Finnish)	~27k	1 in 790	1 in 1,800
Admixed American	~22k	1 in 110	1 in 450
African / African American	~21k	1 in 64	1 in 510
East Asian	~20k	1 in 150	1 in 860
Ashkenazi Jewish	~13k	1 in 310	≈ 1 in 5,400
Middle Eastern	~2,884	1 in 130	1 in 520

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 3 of 4 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: all 4.? see exons ↓