TRPS1

Chr 8AD

transcriptional repressor GATA binding 1

Also known as: GC79, LGCR

NCBI Gene: 7227 ENSG00000104447 UniProt: Q9UHF7 OMIM: 604386

The protein encoded by this gene is a transcription factor that represses GATA-regulated genes, with its activity modulated through binding to dynelin light chain proteins. Mutations cause trichorhinophalangeal syndrome types I and III through an autosomal dominant inheritance pattern. The pathogenic mechanism involves loss of function of this transcriptional repressor.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a transcription factor that represses GATA-regulated genes and binds to a dynein light chain protein. Binding of the encoded protein to the dynein light chain protein affects binding to GATA consensus sequences and suppresses its transcriptional activity. Defects in this gene are a cause of tricho-rhino-phalangeal syndrome (TRPS) types I-III. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.113 OMIM phenotypes

Clinical Summary— TRPS1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

184 unique Pathogenic / Likely Pathogenic· 365 VUS of 851 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TRPS1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.11LOEUF

pLI 1.000

Z-score 5.92

OE 0.02 (0.01–0.11)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

1.54Z-score

OE missense 0.83 (0.78–0.89)

562 obs / 674.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.11)

0≤0.351.4

Missense OE?0.83 (0.78–0.89)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 1 / 42.9Missense obs/exp: 562 / 674.8Syn Z: -0.60

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveTRPS1-related trichorhinopharangeal syndromeLOFAD

This gene — mechanism propensity

0.2299th %ile

GOF

0.2098th %ile

LOF

0.87top 5%

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

LOFprediction above median · 1 literature citation · 84% of P/LP variants are LoF · LOEUF 0.11 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

Literature Evidence

DNThe patient with type I TRPS had haploinsufficiency of TRPS1, whereas the patient with type III TRPS had an allele causing functional modification of the GATA-type motif, possibly inducing a dominant-negative effect on DNA transcription regulation and leading to a more severe phenotype.1

LOFLanger-Giedion's syndrome (LGS) or trichorhinophalangeal syndrome type II (TRPS II; MIM:150230) is a contiguous gene deletion syndrome caused by the haploinsufficiency of the TRPS1 and EXT1 genes.2

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

References

ClinVar Variant Classifications

851 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic136

Likely Pathogenic48

VUS365

Likely Benign189

Benign50

Conflicting32

136

Pathogenic

Likely Pathogenic

365

VUS

189

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	123	6	7	0	136
Likely Pathogenic	32	15	1	0	48
VUS	5	352	6	2	365
Likely Benign	0	45	16	128	189
Benign	0	8	24	18	50
Conflicting	—				32
Total	160	426	54	148	820

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

View in ClinVar →

63 pathogenic / likely-pathogenic (of 67) ClinVar copy-number / structural variants overlap TRPS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →