HNRNPH1

protein-coding

heterogeneous nuclear ribonucleoprotein H1, the group of RNA binding motif containing|Heterogeneous nuclear ribonucleoproteins

Gene summary

This gene encodes a member of a subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs). The hnRNPs are RNA binding proteins that complex with heterogeneous nuclear RNA. These proteins are associated with pre-mRNAs in the nucleus and appear to influence pre-mRNA processing and other aspects of mRNA metabolism and transport. While all of the hnRNPs are present in the nucleus, some may shuttle between the nucleus and the cytoplasm. The hnRNP proteins have distinct nucleic acid binding properties. The protein encoded by this gene has three repeats of quasi-RRM domains that bind to RNA and is very similar to the family member HNRPF. This gene may be associated with hereditary lymphedema type I. Alternatively spliced transcript variants have been described [provided by RefSeq, Mar 2012]

Previous symbols:

HNRPH1

MANE transcript

NM_001257293.2

Inheritance

ClinVar variants

P:10U:74B:11

Top phenotype

syndromic intellectual disability

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr5:179,614,178-179,634,784

External References & Databases

Ensembl (ENSG00000169045)

Transcript & Mutation Effects

hg38 • Region Span ~20.6 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorder with craniofacial dysmorphism and skeletal defectsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859301

Submitter: Labcorp Genetics (formerly Invitae)

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

syndromic intellectual disabilityDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0000508

Submitter: ClinGen

*HNRNPH1* was first reported in relation to autosomal dominant syndromic intellectual disability in 2018 (Pilch et al., PMID: 29938792). The authors reported a male proband with a *de novo* p.Arg206Trp variant, which is analogous to the recurrent *HNRNPH2* variant associated with HNRNPH2-related X-linked intellectual disability, Bain type. Affected individuals present with syndromic intellectual disability, dysmorphic facial features, absent or minimal verbal skills, brain abnormalities, ophthalmological abnormalities, genitourinary malformations, short stature, microcephaly, and hypotonia. Eight *de novo* variants (4 missense, 1 in-frame deletion, 2 frameshift, and 1 splice) reported in ten probands in five publications (PMIDs: 23934111, 29938792, 32335897, 32685970, 33874999) are included in this curation. Four probands had missense variants affecting the Arg206 mutational hotspot within the nuclear localization signal, including three with p.Arg206Trp. Additional cases with *HNRNPH1* *de novo* variants have been reported, but they were not included in this curation because individual phenotype information was not provided (PMIDs: 33057194, 33077954). Pathogenic *HNRNPH1* missense variants, particularly in the nuclear localization signal, may disrupt nuclear import and nucleic acid binding, leading to cytoplasmic accumulation and a possible toxic gain- or complex loss-of-function mechanism (PMIDs: 20308327, 40591994). Loss-of-function variants likely act through haploinsufficiency (PMIDs: 23934111, 32335897). This gene-disease relationship is also supported by the biochemical function of HNRNPH1 and protein interaction. HNRNPH1 belongs to the heterogeneous nuclear ribonucleoprotein (HNRNP) gene family, which regulates mRNA processing mechanisms, including RNA splicing; several genes in this family (*HNRNPC*, *HNRNPD*, *HNRNPH2*, *HNRNPK*, *SYNCRIP* [also known as *HNRNPQ*], *HNRNPR*, and *HNRNPU*) have been implicated in syndromic intellectual disability (PMID: 33874999). In summary, there is definitive evidence supporting the relationship between *HNRNPH1* and autosomal dominant syndromic intellectual disability. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 16, 2024 (SOP Version 11).

neurodevelopmental disorder with craniofacial dysmorphism and skeletal defectsSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859301

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HNRNPH1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 51

Inborn genetic diseasesTotal: 25

Neurodevelopmental disorder with craniofacial dysmorphism and skeletal defectsTotal: 13

not specifiedTotal: 10

HNRNPH1-related disorderTotal: 5

HNRNPH1-related disordersTotal: 2

Neurodevelopmental disorderTotal: 1

Intellectual disability, X-linked, syndromic, Bain typeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001257293.2. 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				9 clinvar	2 clinvar	11
missense	3 clinvar	1 clinvar	64 clinvar			68
nonsense		1 clinvar				1
start loss			1 clinvar			1
frameshift	2 clinvar	3 clinvar	4 clinvar			9
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	5	5	74	9	2	95

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 216 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001257293.2	RefSeq	NP_001244222.1	12	MANE Select
ENST00000393432.9	Ensembl	ENSP00000377082.4	12	MANE Select
NM_001363572.2	RefSeq	NP_001350501.1	11	Standard
NM_001364225.2	RefSeq	NP_001351154.1	12	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

MECP2 and Associated Rett Syndrome
mRNA Processing
FGFR2 alternative splicing
Signaling by FGFR2
Signal Transduction

Biological Process

mRNA splicing, via spliceosome
RNA processing
fibroblast growth factor receptor signaling pathway
RNA metabolic process
regulation of RNA splicing

Molecular Function

RNA binding
protein binding
poly(U) RNA binding

Cellular Component

nucleus
nucleoplasm
cytosol
membrane
catalytic step 2 spliceosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000356731
Coding exons: 12
Length: 20607
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 2
Defined: 125734
p: 0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.09	74	259	0.285	0.0000134	2963
Missense (PolyPhen)		14	64.594	0.21674		814
Synonymous	-0.0754	90	89.1	1.01	0.00000495	826
Loss of Function	4.84	0	27.3	0.00	0.00000143	326

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: This protein is a component of the heterogeneous nuclear ribonucleoprotein (hnRNP) complexes which provide the substrate for the processing events that pre-mRNAs undergo before becoming functional, translatable mRNAs in the cytoplasm. Mediates pre-mRNA alternative splicing regulation. Inhibits, together with CUGBP1, insulin receptor (IR) pre-mRNA exon 11 inclusion in myoblast. Binds to the IR RNA. Binds poly(RG). {ECO:0000269|PubMed:11003644, ECO:0000269|PubMed:16946708}.;

Intolerance Scores

LoFtool: 0.0638
RVIS EVS: -0.27
RVIS percentile EVS: 33.97

Essentials

Essential (CRISPR): N
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.958

Gene Damage Prediction

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