TTC4

Chr 1

tetratricopeptide repeat domain 4

Also known as: CNS1

NCBI Gene: 7268 ENSG00000243725 UniProt: O95801 OMIM: 606753

The protein functions as a co-chaperone that recruits Hsp90 and Hsp70 molecular chaperones to nascent polypeptides, facilitating proper protein folding and supporting cellular translation through interaction with elongation factor eEF2. Mutations in TTC4 cause autosomal recessive intellectual disability with microcephaly, short stature, and facial dysmorphism. The gene shows tolerance to loss-of-function variants, consistent with the recessive inheritance pattern observed in affected individuals.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a protein that contains tetratricopeptide (TPR) repeats, which often mediate protein-protein interactions and chaperone activity. The encoded protein interacts with heat shock proteins 70 and 90. Alternative splicing results in multiple transcript variants. Naturally-occuring readthrough transcription occurs from upstream gene MROH (maestro heat-like repeat family member 7) to this gene. [provided by RefSeq, Apr 2014]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.90

Clinical Summary— TTC4

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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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ClinVar Variants

41 VUS of 44 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.90LOEUF

pLI 0.000

Z-score 1.92

OE 0.55 (0.35–0.90)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.25Z-score

OE missense 0.95 (0.84–1.07)

188 obs / 198.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.55 (0.35–0.90)

0≤0.351.4

Missense OE?0.95 (0.84–1.07)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 12 / 21.7Missense obs/exp: 188 / 198.0Syn Z: 0.55

This gene — mechanism propensity

0.78top 25%

GOF

0.6247th %ile

LOF

0.2092th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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.

ClinVar Variant Classifications

44 submitted variants in ClinVar

ClinVar

Classification Summary

VUS41

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	41	41
Likely Benign	2	2
Benign	0	0
Total	43	43

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap TTC4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →