DENND4A

Chr 15

DENN domain containing 4A

Also known as: IRLB, MYCPBP

NCBI Gene: 10260 ENSG00000174485 UniProt: Q7Z401

This gene encodes a DENN domain-containing protein that may function as a guanine nucleotide exchange factor that specifically activates ras-related protein Rab-10. This protein also contains a interferon stimulated response element-binding domain and may be involved in regulating the v-myc avian myelocytomatosis viral (MYC) oncogene. Alternate splicing results in multiple transcript variants. A pseudogene of this gene is found on chromosome 8. [provided by RefSeq, Mar 2016]

Research

ResearchGenerating clinical summary…

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

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P/LP missense

0.28

LOEUF· LoF intol.

LOF

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

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.28LOEUF

pLI 0.996

Z-score 6.89

OE 0.18 (0.12–0.28)

Highly constrained

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

Missense Constraint?

3.67Z-score

OE missense 0.66 (0.62–0.71)

622 obs / 938.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.18 (0.12–0.28)

0≤0.351.4

Missense OE?0.66 (0.62–0.71)

0≤0.61.4

Synonymous OE?0.83

0≤1.21.6

LoF obs/exp: 15 / 82.6Missense obs/exp: 622 / 938.8Syn Z: 2.45

Background carrier burden — how many people carry a rare variant somewhere in DENND4A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 50

1,864 rare PASS variants

Rare truncating (LoF)

1 in 1,600

160 rare PASS variants

Rare synonymous (reference)

1 in 67

733 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DENND4A. 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 54	1 in 1,500
South Asian	~43k	1 in 41	1 in 2,400
Remaining (unassigned)	~30k	1 in 43	1 in 2,000
European (Finnish)	~27k	1 in 100	1 in 3,300
Admixed American	~22k	1 in 42	1 in 1,500
African / African American	~21k	1 in 46	1 in 1,300
East Asian	~20k	1 in 44	1 in 1,300
Ashkenazi Jewish	~13k	1 in 150	≈ 1 in 4,300
Middle Eastern	~2,884	1 in 53	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): 26 of 31 coding exons well covered in gnomAD exomes; exons 8, 9, 21, 26, 32 marginal. Genomes: all 31.? see exons ↓