GTF2IRD1

Chr 7

GTF2I repeat domain containing 1

Also known as: BEN, CREAM1, GTF3, MUSTRD1, RBAP2, WBS, WBSCR11, WBSCR12

NCBI Gene: 9569 ENSG00000006704 UniProt: Q9UHL9

This protein functions as a transcription regulator involved in craniofacial and cognitive development, cell-cycle progression, and skeletal muscle differentiation. Mutations cause Williams-Beuren syndrome, a multisystem developmental disorder with craniofacial abnormalities and intellectual disability that follows an autosomal dominant inheritance pattern due to deletions at 7q11.23. The gene is highly constrained against loss-of-function variants (pLI 0.90, LOEUF 0.33), indicating that complete loss of protein function is likely deleterious.

GeneReviews ResearchSummary from RefSeq, UniProt

The protein encoded by this gene contains five GTF2I-like repeats and each repeat possesses a potential helix-loop-helix (HLH) motif. It may have the ability to interact with other HLH-proteins and function as a transcription factor or as a positive transcriptional regulator under the control of Retinoblastoma protein. This gene plays a role in craniofacial and cognitive development and mutations have been associated with Williams-Beuren syndrome, a multisystem developmental disorder caused by deletion of multiple genes at 7q11.23. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2010]

GeneReviews ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.33

Clinical Summary— GTF2IRD1

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.90). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 127 VUS of 231 total submissions

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GeneReview available — GTF2IRD1

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.33LOEUF

pLI 0.900

Z-score 5.36

OE 0.19 (0.12–0.33)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

2.66Z-score

OE missense 0.70 (0.65–0.76)

444 obs / 632.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.19 (0.12–0.33)

0≤0.351.4

Missense OE?0.70 (0.65–0.76)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 10 / 51.5Missense obs/exp: 444 / 632.2Syn Z: 0.33

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedGTF2IRD1-related neurodevelopmental disorderOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.4587th %ile

GOF

0.4382th %ile

LOF

0.72top 10%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

231 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic1

VUS127

Likely Benign53

Benign17

Conflicting1

Pathogenic

Likely Pathogenic

127

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	1	0	1
Likely Pathogenic	0	1	0	0	1
VUS	3	124	0	0	127
Likely Benign	0	10	3	40	53
Benign	0	1	3	13	17
Conflicting	—				1
Total	3	136	7	53	200

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

View in ClinVar →

166 pathogenic / likely-pathogenic (of 178) ClinVar copy-number / structural variants overlap GTF2IRD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →