TPSD1

Chr 16

tryptase delta 1

Also known as: MCP7-LIKE, MCP7L1, MMCP-7L

NCBI Gene: 23430 ENSG00000095917 OMIM: 609272

Tryptase delta-1 is a trypsin-like serine protease that functions as the major neutral protease in mast cells and is secreted during mast cell activation and degranulation. The gene shows very low constraint against loss-of-function variants (pLI near 0, high LOEUF of 1.85), indicating tolerance to protein-truncating mutations. Clinical associations with TPSD1 mutations in pediatric neurological disorders have not been established in the current literature.

OMIM ResearchSummary from RefSeq, UniProt

Tryptases comprise a family of trypsin-like serine proteases, the peptidase family S1. Tryptases are enzymatically active only as heparin-stabilized tetramers, and they are resistant to all known endogenous proteinase inhibitors. Several tryptase genes are clustered on chromosome 16p13.3. These genes are characterized by several distinct features. They have a highly conserved 3' UTR and contain tandem repeat sequences at the 5' flank and 3' UTR which are thought to play a role in regulation of the mRNA stability. Although this gene may be an exception, most of the tryptase genes have an intron immediately upstream of the initiator Met codon, which separates the site of transcription initiation from protein coding sequence. This feature is characteristic of tryptases but is unusual in other genes. Tryptases have been implicated as mediators in the pathogenesis of asthma and other allergic and inflammatory disorders. This gene was once considered to be a pseudogene, although it is now believed to be a functional gene that encodes a protein. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.85

Clinical Summary— TPSD1

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.85LOEUF

pLI 0.000

Z-score -0.95

OE 1.30 (0.86–1.85)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.62Z-score

OE missense 1.37 (1.22–1.54)

208 obs / 151.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.30 (0.86–1.85)

0≤0.351.4

Missense OE?1.37 (1.22–1.54)

0≤0.61.4

Synonymous OE?1.37

0≤1.21.6

LoF obs/exp: 15 / 11.5Missense obs/exp: 208 / 151.7Syn Z: -2.47

This gene — mechanism propensity

0.6842th %ile

GOF

0.76top 25%

LOF

0.3164th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

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.

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