RNF6

Chr 13

ring finger protein 6

NCBI Gene: 6049 ENSG00000127870 UniProt: Q9Y252

RNF6 encodes an E3 ubiquitin-protein ligase that mediates polyubiquitination and proteasomal degradation of multiple proteins including LIMK1, androgen receptor, and QKI, thereby regulating axonal outgrowth and transcriptional activity. Mutations in this gene cause esophageal carcinoma with somatic inheritance pattern. The gene shows tolerance to loss-of-function variants (pLI = 0.014, LOEUF = 0.526), suggesting that complete loss of function may be compatible with normal development.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene contains a RING-H2 finger motif. Deletions and mutations in this gene were detected in esophageal squamous cell carcinoma (ESCC), suggesting that this protein may be a potential tumor suppressor. Studies of the mouse counterpart suggested a role of this protein in the transcription regulation that controls germinal differentiation. Multiple alternatively spliced transcript variants encoding the same protein are observed. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtEsophageal cancer

Clinical highlights

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.53

LOEUF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.53LOEUF

pLI 0.014

Z-score 3.53

OE 0.30 (0.18–0.53)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.25Z-score

OE missense 0.82 (0.75–0.90)

310 obs / 378.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.18–0.53)

0≤0.351.4

Missense OE?0.82 (0.75–0.90)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 9 / 29.8Missense obs/exp: 310 / 378.3Syn Z: 0.37

Background carrier burden — how many people carry a rare variant somewhere in RNF6?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 78

752 rare PASS variants

Rare truncating (LoF)

1 in 3,800

59 rare PASS variants

Rare synonymous (reference)

1 in 100

273 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RNF6. 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 79	1 in 3,300
South Asian	~43k	1 in 86	1 in 2,900
Remaining (unassigned)	~30k	1 in 57	1 in 5,000
European (Finnish)	~27k	1 in 560	≈ 1 in 6,700
Admixed American	~22k	1 in 72	≈ 1 in 7,500
African / African American	~21k	1 in 65	≈ 1 in 6,400
East Asian	~20k	1 in 130	≈ 1 in 5,000
Ashkenazi Jewish	~13k	1 in 260	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 73	none seen

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): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓