ACD

Chr 16ADAR

ACD shelterin complex subunit and telomerase recruitment factor

Also known as: DKCA6, DKCB7, PIP1, PTOP, TINT1, TPP1

NCBI Gene: 65057 ENSG00000102977 UniProt: Q96AP0

This gene encodes a protein that is involved in telomere function. This protein is one of six core proteins in the telosome/shelterin telomeric complex, which functions to maintain telomere length and to protect telomere ends. Through its interaction with other components, this protein plays a key role in the assembly and stabilization of this complex, and it mediates the access of telomerase to the telomere. Multiple transcript variants encoding different isoforms have been found for this gene. This gene, which is also referred to as TPP1, is distinct from the unrelated TPP1 gene on chromosome 11, which encodes tripeptidyl-peptidase I. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

?Dyskeratosis congenita, autosomal dominant 6MIM #616553

ADAR

?Dyskeratosis congenita, autosomal recessive 7MIM #616553

ADAR

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

-0.5

Missense Z

1.19

LOEUF

Clinical Summary— ACD

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Gene-Disease Validity (ClinGen)

ACD-related short telomere syndrome · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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Clinical Trials

6 active or recruiting trials — potential therapeutic options may be available

Some data sources returned errors (1)

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

1.19LOEUF

pLI 0.000

Z-score 0.82

OE 0.82 (0.58–1.19)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-0.49Z-score

OE missense 1.08 (0.98–1.18)

345 obs / 320.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.82 (0.58–1.19)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.08 (0.98–1.18)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.20

0≤1.21.6

LoF obs/exp: 21 / 25.5Missense obs/exp: 345 / 320.5Syn Z: -1.88

0.4785th %ile

GOF

0.4776th %ile

LOF

0.4331th %ile

The Badonyi & Marsh model scores gain-of-function highest, but genomic evidence most strongly supports dominant-negative as the primary mechanism.

DN1 literature citation

Literature Evidence

DNThe autosomal-dominant ACD associated mutation p.C413S played its pathogenic role through a dominant-negative effect on wild-type GPNMB.PMID:34551863

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