ZNF687

Chr 1AD

zinc finger protein 687

Also known as: PDB6

NCBI Gene: 57592 ENSG00000143373 UniProt: Q8N1G0 OMIM: 610568

This gene encodes C2H2 zinc finger protein. The encoded protein may play a role in bone differentiation and development. Mutations in this gene are the cause of Paget disease of bone-6. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

OMIM Research

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.321 OMIM phenotype

Clinical Summary— ZNF687

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 370 VUS of 601 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.32LOEUF

pLI 0.971

Z-score 4.52

OE 0.15 (0.08–0.32)

Highly constrained

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

Missense Constraint?

1.81Z-score

OE missense 0.81 (0.76–0.87)

609 obs / 748.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.08–0.32)

0≤0.351.4

Missense OE?0.81 (0.76–0.87)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 5 / 33.0Missense obs/exp: 609 / 748.2Syn Z: -1.37

This gene — mechanism propensity

0.3296th %ile

GOF

0.2995th %ile

LOF

0.79top 5%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · LOEUF 0.32

GOF1 literature citation

Literature Evidence

GOFWe also found a parallel increase of ZNF687 in the nuclear fraction, suggesting that c.2810C>G acts as gain-of-function mutation, altering the nuclear-cytoplasmic balance of ZNF687, thus leading to enhanced availability of this transcription factor in the nucleus.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 26849110 ↗

ClinVar Variant Classifications

601 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS370

Likely Benign186

Benign23

Conflicting9

Pathogenic

370

VUS

186

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	0	1
Likely Pathogenic	0	0	0	0	0
VUS	9	352	7	2	370
Likely Benign	0	7	31	148	186
Benign	0	8	4	11	23
Conflicting	—				9
Total	9	368	42	161	589

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 19) ClinVar copy-number / structural variants overlap ZNF687 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →