HNRNPU

Chr 1AD

heterogeneous nuclear ribonucleoprotein U

Also known as: DEE54, EIEE54, GRIP120, HNRNPU-AS1, HNRPU, SAF-A, SAFA, U21.1

NCBI Gene: 3192 ENSG00000153187 UniProt: Q00839 OMIM: 602869

The protein binds heterogeneous nuclear RNA and scaffold-attached region DNA to form ribonucleoprotein complexes in the nucleus. Loss-of-function mutations cause developmental and epileptic encephalopathy 54 through autosomal dominant inheritance. The gene is highly intolerant to loss-of-function variants, consistent with haploinsufficiency as the disease mechanism.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of a family of proteins that bind nucleic acids and function in the formation of ribonucleoprotein complexes in the nucleus with heterogeneous nuclear RNA (hnRNA). The encoded protein has affinity for both RNA and DNA, and binds scaffold-attached region (SAR) DNA. Mutations in this gene have been associated with epileptic encephalopathy, early infantile, 54. A pseudogene of this gene has been identified on chromosome 14. [provided by RefSeq, Jun 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 54MIM #617391

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · complex neurodevelopmental disorder · AD · ClinGen 2022
Definitive · developmental and epileptic encephalopathy, 54 · AD · G2P

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.11

LOEUF· LoF intol.

LOF

Mechanism· G2P

📖

GeneReview available — HNRNPU

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.11LOEUF

pLI 1.000

Z-score 5.84

OE 0.02 (0.01–0.11)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

3.37Z-score

OE missense 0.56 (0.50–0.62)

253 obs / 455.5 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.02 (0.01–0.11)

0≤0.351.4

Missense OE?0.56 (0.50–0.62)

0≤0.61.4

Synonymous OE?1.28

0≤1.21.6

LoF obs/exp: 1 / 41.7Missense obs/exp: 253 / 455.5Syn Z: -2.83

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

821 rare PASS variants

Rare truncating (LoF)

1 in 550

56 rare PASS variants

Rare synonymous (reference)

1 in 150

479 rare PASS variants

Rare missense and truncating variants are carried at similar rates in HNRNPU; this gene does not show strong loss-of-function constraint by this measure. 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 170	1 in 790
South Asian	~43k	1 in 100	1 in 770
Remaining (unassigned)	~30k	1 in 83	1 in 650
European (Finnish)	~27k	1 in 160	1 in 1,600
Admixed American	~22k	1 in 100	1 in 790
African / African American	~21k	1 in 88	1 in 2,000
East Asian	~20k	1 in 85	1 in 1,300
Ashkenazi Jewish	~13k	1 in 660	1 in 2,600
Middle Eastern	~2,884	1 in 140	1 in 540

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 10 of 14 coding exons well covered in gnomAD exomes; exons 4, 5, 6, 14 marginal. Genomes: all 14.? see exons ↓