TSHZ1

Chr 18AD

teashirt zinc finger homeobox 1

Also known as: CAA, NY-CO-33, SDCCAG33, TSH1

This gene encodes a zinc-finger transcriptional regulator involved in developmental processes. Mutations cause congenital aural atresia syndrome with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variation (pLI 0.997), suggesting mutations likely have significant developmental consequences.

Summary from RefSeq, OMIM, UniProt
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Primary Disease Associations & Inheritance

Aural atresia, congenitalMIM #607842
AD
0
Active trials
3
Pubs (1 yr)
155
P/LP submissions
0%
P/LP missense
0.24
LOEUF· LoF intol.
LOF
Mechanism· G2P
Clinical SummaryTSHZ1
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Gene-Disease Validity (ClinGen)
aural atresia, congenital · ADLimited

Limited evidence — not for standalone diagnostic reporting

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
153 unique Pathogenic / Likely Pathogenic· 207 VUS of 423 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.24LOEUF
pLI 0.997
Z-score 4.38
OE 0.08 (0.030.24)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint
1.29Z-score
OE missense 0.86 (0.800.92)
553 obs / 645.4 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.08 (0.030.24)
00.351.4
Missense OE0.86 (0.800.92)
00.61.4
Synonymous OE1.09
01.21.6
LoF obs/exp: 2 / 26.2Missense obs/exp: 553 / 645.4Syn Z: -1.27
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
limitedTSHZ1-related aural atresia, congenitalLOFAD
DN
0.2599th %ile
GOF
0.2298th %ile
LOF
0.86top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.24

Literature Evidence

LOFTogether, these results demonstrate that hemizygosity of TSHZ1 leads to congenital aural atresia as a result of haploinsufficiency.PMID:22152683

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

ClinVar Variant Classifications

423 submitted variants in ClinVar

Classification Summary

Pathogenic145
Likely Pathogenic8
VUS207
Likely Benign41
Benign17
145
Pathogenic
8
Likely Pathogenic
207
VUS
41
Likely Benign
17
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
145
0
145
Likely Pathogenic
1
0
7
0
8
VUS
1
193
13
0
207
Likely Benign
1
18
0
22
41
Benign
0
7
0
10
17
Total321816532418

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

View in ClinVar →

Protein Context — Lollipop Plot

TSHZ1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
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