HNRNPR

Chr 1AD

heterogeneous nuclear ribonucleoprotein R

Also known as: HNRPR, NEDDFSB, hnRNP-R

NCBI Gene: 10236 ENSG00000125944 UniProt: O43390 OMIM: 607201

This gene encodes an RNA-binding protein that is a component of the spliceosome C complex and functions in pre-mRNA processing within ribonucleoprotein complexes. Mutations cause a neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities, inherited in an autosomal dominant pattern. The gene is highly constrained against loss-of-function variants (pLI 0.999, LOEUF 0.21), indicating that heterozygous variants are likely pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes an RNA-binding protein that is a member of the spliceosome C complex, which functions in pre-mRNA processing and transport. The encoded protein also promotes transcription at the c-fos gene. Alternative splicing results in multiple transcript variants. There are pseudogenes for this gene on chromosomes 4, 11, and 10. [provided by RefSeq, Jul 2014]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalitiesMIM #620073

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · syndromic intellectual disability · AD · ClinGen 2023

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

0.21

LOEUF· LoF intol.

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.21LOEUF

pLI 0.999

Z-score 4.74

OE 0.07 (0.03–0.21)

Highly constrained

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

Missense Constraint?

3.54Z-score

OE missense 0.48 (0.42–0.54)

174 obs / 364.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.07 (0.03–0.21)

0≤0.351.4

Missense OE?0.48 (0.42–0.54)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 2 / 30.0Missense obs/exp: 174 / 364.0Syn Z: 0.93

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 240

463 rare PASS variants

Rare truncating (LoF)

1 in 17,000

20 rare PASS variants

Rare synonymous (reference)

1 in 260

253 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HNRNPR. 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 280	1 in 17,000
South Asian	~43k	1 in 200	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 220	≈ 1 in 30,000
European (Finnish)	~27k	1 in 420	none seen
Admixed American	~22k	1 in 390	≈ 1 in 5,600
African / African American	~21k	1 in 280	none seen
East Asian	~20k	1 in 200	none seen
Ashkenazi Jewish	~13k	1 in 970	≈ 1 in 13,000
Middle Eastern	~2,884	≈ 1 in 1,400	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): 8 of 10 coding exons well covered in gnomAD exomes; exons 3, 5 marginal. Genomes: all 10.? see exons ↓