INTS6

Chr 13AD

integrator complex subunit 6

Also known as: DBI-1, DDX26, DDX26A, DICE1, HDB, INT6, MRD78, Notchl2

NCBI Gene: 26512 ENSG00000102786 OMIM: 604331

INTS6 encodes a component of the integrator complex that regulates RNA polymerase II transcription termination and processes small nuclear RNAs, acting as a molecular adapter to recruit protein phosphatase 2A to transcription checkpoints. Mutations cause autosomal dominant developmental delay with variable intellectual disability and behavioral abnormalities, typically presenting in early childhood. This gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely incompatible with normal development.

OMIM ResearchSummary from RefSeq, UniProt

DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. The protein encoded by this gene is a DEAD box protein that is part of a complex that interacts with the C-terminus of RNA polymerase II and is involved in 3' end processing of snRNAs. In addition, this gene is a candidate tumor suppressor and is located in the critical region of loss of heterozygosity (LOH). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2015]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.141 OMIM phenotype

Clinical Summary— INTS6

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.14LOEUF

pLI 1.000

Z-score 6.03

OE 0.04 (0.02–0.14)

Highly constrained

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

Missense Constraint?

3.83Z-score

OE missense 0.50 (0.45–0.56)

233 obs / 465.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.04 (0.02–0.14)

0≤0.351.4

Missense OE?0.50 (0.45–0.56)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 2 / 46.3Missense obs/exp: 233 / 465.7Syn Z: -1.05

This gene — mechanism propensity

0.3792th %ile

GOF

0.3788th %ile

LOF

0.78top 5%

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

LOFprediction above median · LOEUF 0.14

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