HNRNPR

protein-coding

heterogeneous nuclear ribonucleoprotein R, the group of RNA binding motif containing|Heterogeneous nuclear ribonucleoproteins

Gene summary

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]

Previous symbols:

HNRPR

MANE transcript

NM_005826.5

Inheritance

ClinVar variants

P:8U:93B:11

Top phenotype

Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalities

gnomAD constraint

pLI —, LoF o/e 0.07

Max pathogenic AF

—

Genomic locus

chr1:23,303,771-23,344,336

External References & Databases

Ensembl (ENSG00000125944)

Transcript & Mutation Effects

hg38 • Region Span ~40.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859297

Submitter: Labcorp Genetics (formerly Invitae)

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

The *HNRNPR* gene encodes a member of the spliceosome C complex, which functions in pre-mRNA processing and transport. Although the first *HNRNPR* variant was observed in a large epilepsy cohort in 2016 (PMID: 26795593), *HNRNPR* was first reported in relation to syndromic intellectual disability in 2019 by Duijkers et al. (PMID: 31079900). Overlapping clinical characteristics in 5 reported individuals included developmental delay/intellectual disability, microcephaly, seizures, facial dysmorphism, brachydactyly, and other congenital abnormalities. At least 6 variants have been reported in 9 probands, including 1 splice-site, 3 frameshift, 1 nonsense, and 1 missense variants (PMIDs: 26795593, 31079900, 33874999). Variants were de novo in all instances in which parental DNA was available. A frameshift and a missense variant were recurrent, identified in two and three unrelated probands, respectively. Other reported missense variants without functional characterization were of unclear pathogenicity and were not scored (PMID: 33874999). Other members of the heterogeneous nuclear ribonucleoprotein (HNRNP) gene family have been recently implicated in neurodevelopmental disorders (*HNRNPK*, *HNRNPU*, *HNRNPH1*, *HNRNPH2*, and *HNRNPR*) (PMID: 33874999), supporting this gene-disease relationship. In summary, there is definitive evidence supporting the relationship between *HNRNPR* and syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on May 3, 2023 (SOP Version 9).

neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalitiesSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859297

Submitter: PanelApp Australia

neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalitiesDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0859297

Submitter: G2P

Clinical Genomic Database (CGD)

Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalitiesAD

Manifestation: Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 31079900

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HNRNPR variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 49

not providedTotal: 41

Neurodevelopmental disorder with dysmorphic facies and skeletal and brain abnormalitiesTotal: 9

not specifiedTotal: 4

HNRNPR-related disorderTotal: 3

Neurodevelopmental disorderTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005826.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	4 clinvar		5
missense	1 clinvar	1 clinvar	81 clinvar	7 clinvar		90
nonsense		2 clinvar	2 clinvar			4
start loss						0
frameshift	4 clinvar		2 clinvar			6
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	5	3	93	11	0	112

Highest pathogenic variant AF is 6.842613e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 83 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005826.5	RefSeq	NP_005817.1	10	MANE Select
ENST00000302271.11	Ensembl	ENSP00000304405.6	10	MANE Select
NM_001102397.3	RefSeq	NP_001095867.1	8	Standard
NM_001102398.3	RefSeq	NP_001095868.1	10	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
hnrnpr	Danio rerio	Structure: CaP motoneuron Quality: increased branchiness abnormal

Gene / Model

Organism

Observed Phenotype

hnrnpr

Danio rerio

Structure: CaP motoneuron

Quality: increased branchiness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

mRNA Processing
Metabolism of RNA
mRNA Splicing - Major Pathway
EGFR1
mRNA Splicing

Biological Process

mRNA splicing, via spliceosome
mRNA processing
circadian rhythm
RNA metabolic process
negative regulation of catalytic activity

Molecular Function

RNA binding
mRNA binding
mRNA 3'-UTR binding
protein binding

Cellular Component

nucleus
nucleoplasm
spliceosomal complex
nucleolus
endoplasmic reticulum

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374616
Coding exons: 10
Length: 40566
Individuals with no LoFs: 125575
Homozygous LoFs: 0
Heterozygous LoFs: 173
Defined: 125748
p: 0.000688

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.54	174	364	0.478	0.0000200	4143
Missense (PolyPhen)		30	116.58	0.25734		1504
Synonymous	0.927	112	125	0.895	0.00000682	1213
Loss of Function	4.74	2	30.0	0.0667	0.00000145	398

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0026	0.0024	notable
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00061	0.00060	rare
Finnish	0.00085	0.00083	rare
European (Non-Finnish)	0.00081	0.00079	rare
South Asian	0.00010	0.000098	rare
Other	0.0010	0.00098	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of ribonucleosomes, which are complexes of at least 20 other different heterogenious nuclear ribonucleoproteins (hnRNP). hnRNP play an important role in processing of precursor mRNA in the nucleus.;

Recessive Scores

pRec: 0.276

Intolerance Scores

LoFtool: 0.0907
RVIS EVS: -0.45
RVIS percentile EVS: 24

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.942

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium