INTS1

Chr 7AR

integrator complex subunit 1

Also known as: INT1, NDCAGF, NET28

NCBI Gene: 26173 ENSG00000164880 UniProt: Q8N201 OMIM: 611345

INTS1 encodes a subunit of the Integrator complex that terminates RNA polymerase II transcription and processes small nuclear RNAs, with the gene being highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.476). Mutations cause autosomal recessive neurodevelopmental disorder with intellectual disability and variable features including hypotonia, seizures, and brain abnormalities. The disorder typically presents in infancy with developmental delays and affects the central nervous system primarily.

OMIM ResearchSummary from RefSeq, UniProt

INTS1 is a subunit of the Integrator complex, which associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A; MIM 180660) and mediates 3-prime end processing of small nuclear RNAs U1 (RNU1; MIM 180680) and U2 (RNU2; MIM 180690) (Baillat et al., 2005 [PubMed 16239144]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic faciesMIM #618571

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Neurodevelopmental disorder with cataracts, poor growth, and dysmorphic facies; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.48

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.48LOEUF

pLI 0.000

Z-score 5.98

OE 0.36 (0.28–0.48)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.41Z-score

OE missense 0.89 (0.85–0.94)

1208 obs / 1353.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.36 (0.28–0.48)

0≤0.351.4

Missense OE?0.89 (0.85–0.94)

0≤0.61.4

Synonymous OE?1.32

0≤1.21.6

LoF obs/exp: 37 / 102.2Missense obs/exp: 1208 / 1353.9Syn Z: -6.22

Background carrier burden — how many people carry a rare variant somewhere in INTS1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 17

3,256 rare PASS variants

Rare truncating (LoF)

1 in 630

337 rare PASS variants

Rare synonymous (reference)

1 in 20

1,782 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for INTS1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 23	1 in 680
South Asian	~43k	1 in 16	1 in 530
Remaining (unassigned)	~30k	1 in 17	1 in 440
European (Finnish)	~27k	1 in 41	1 in 540
Admixed American	~22k	1 in 16	1 in 330
African / African American	~21k	1 in 17	1 in 560
East Asian	~20k	1 in 19	1 in 740
Ashkenazi Jewish	~13k	1 in 57	1 in 1,400
Middle Eastern	~2,884	1 in 16	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 46 of 47 coding exons well covered in gnomAD exomes; exon 17 marginal. Genomes: 46 of 47 (exon 18 below).? see exons ↓