SIX1

Chr 14AD

SIX homeobox 1

Also known as: BOS3, DFNA23, TIP39

NCBI Gene: 6495 ENSG00000126778 UniProt: Q15475 OMIM: 601205

SIX1 encodes a homeobox transcription factor that regulates cell proliferation, apoptosis, and embryonic development of multiple organs including kidney, muscle, and inner ear. Mutations cause autosomal dominant branchiootic syndrome type 3 (involving branchial arch anomalies, hearing loss, and renal malformations) and autosomal dominant deafness type 23. The gene is moderately constrained against loss-of-function variants (pLI 0.65, LOEUF 0.52).

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in limb development. Defects in this gene are a cause of autosomal dominant deafness type 23 (DFNA23) and branchiootic syndrome type 3 (BOS3). [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.522 OMIM phenotypes

Clinical Summary— SIX1

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Gene-Disease Validity (ClinGen)

branchio-oto-renal syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.65) — some intolerance to loss-of-function variants.

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ClinVar Variants

28 unique Pathogenic / Likely Pathogenic· 156 VUS of 282 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — SIX1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.653

Z-score 2.69

OE 0.17 (0.07–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.19Z-score

OE missense 0.74 (0.63–0.86)

119 obs / 161.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.17 (0.07–0.52)

0≤0.351.4

Missense OE?0.74 (0.63–0.86)

0≤0.61.4

Synonymous OE?1.13

0≤1.21.6

LoF obs/exp: 2 / 12.1Missense obs/exp: 119 / 161.6Syn Z: -0.90

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveSIX1-related deafnessOTHERAD

strongSIX1-related non-syndromic craniosynostosisLOFAD

definitiveSIX1-related branchiootic syndromeOTHERAD

This gene — mechanism propensity

0.5770th %ile

GOF

0.4874th %ile

LOF

0.62top 25%

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

LOF1 literature citation · 32% of P/LP variants are LoF

Literature Evidence

LOFAlthough haploinsufficiency of EYA1 and SIX1 are known to cause BOR, copy number variation analysis has only been performed on a limited number of BOR patients.1

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

References

1.PMID 23851940 ↗

ClinVar Variant Classifications

282 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic19

VUS156

Likely Benign63

Benign12

Conflicting17

Pathogenic

Likely Pathogenic

156

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	6	0	0	9
Likely Pathogenic	6	13	0	0	19
VUS	14	116	23	3	156
Likely Benign	0	2	23	38	63
Benign	0	0	12	0	12
Conflicting	—				17
Total	23	137	58	41	276

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

View in ClinVar →

15 pathogenic / likely-pathogenic (of 21) ClinVar copy-number / structural variants overlap SIX1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →