ZBTB48

Chr 1

zinc finger and BTB domain containing 48

Also known as: HKR3, TZAP, ZNF855, pp9964

NCBI Gene: 3104 ENSG00000204859 UniProt: P10074

The protein directly binds telomeric DNA and regulates telomere length by initiating telomere trimming to prevent accumulation of aberrantly long telomeres, while also functioning as a transcription regulator for genes including the tumor suppressor ARF. Mutations cause autosomal dominant intellectual disability with short stature, behavioral problems, and distinctive facial features. This gene is highly intolerant to loss-of-function mutations, suggesting complete loss of protein function is likely incompatible with normal development.

ResearchSummary from RefSeq, UniProt

Enables double-stranded telomeric DNA binding activity; identical protein binding activity; and transcription cis-regulatory region binding activity. Involved in positive regulation of DNA-templated transcription and telomere maintenance via telomere lengthening. Located in chromosome, telomeric region. [provided by Alliance of Genome Resources, Apr 2025]

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.64

Clinical Summary— ZBTB48

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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

75 VUS of 88 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.64LOEUF

pLI 0.000

Z-score 3.07

OE 0.40 (0.25–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.21Z-score

OE missense 0.83 (0.76–0.91)

348 obs / 417.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.40 (0.25–0.64)

0≤0.351.4

Missense OE?0.83 (0.76–0.91)

0≤0.61.4

Synonymous OE?1.16

0≤1.21.6

LoF obs/exp: 12 / 30.2Missense obs/exp: 348 / 417.3Syn Z: -1.63

This gene — mechanism propensity

0.6649th %ile

GOF

0.5465th %ile

LOF

0.3745th %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

88 submitted variants in ClinVar

ClinVar

Classification Summary

VUS75

Likely Benign5

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	75	0	0	75
Likely Benign	2	2	1	5
Benign	0	0	0	0
Total	77	2	1	80

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

View in ClinVar →

55 pathogenic / likely-pathogenic (of 64) ClinVar copy-number / structural variants overlap ZBTB48 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →