HIRA

protein-coding

histone cell cycle regulator, the group of WD repeat domain containing|HIRA histone chaperone complex subunits

Gene summary

This gene encodes a histone chaperone that preferentially places the variant histone H3.3 in nucleosomes. Orthologs of this gene in yeast, flies, and plants are necessary for the formation of transcriptionally silent heterochomatin. This gene plays an important role in the formation of the senescence-associated heterochromatin foci. These foci likely mediate the irreversible cell cycle changes that occur in senescent cells. It is considered the primary candidate gene in some haploinsufficiency syndromes such as DiGeorge syndrome, and insufficient production of the gene may disrupt normal embryonic development. [provided by RefSeq, Jul 2008]

Previous symbols:

TUPLE1

MANE transcript

NM_003325.4

Inheritance

ClinVar variants

U:125B:42

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr22:19,330,698-19,447,450

External References & Databases

Ensembl (ENSG00000100084)

Transcript & Mutation Effects

hg38 • Region Span ~116.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: G2P

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HIRA variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 113

not providedTotal: 43

HIRA-related disorderTotal: 25

Neurodevelopmental disorderTotal: 2

Prostate cancerTotal: 1

Fanconi anemia complementation group TTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003325.4. 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				27 clinvar	7 clinvar	34
missense			114 clinvar	8 clinvar		122
nonsense						0
start loss			1 clinvar			1
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			9 clinvar			9
Total	0	0	125	35	7	167

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 53 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003325.4	RefSeq	NP_003316.3	25	MANE Select
ENST00000263208.5	Ensembl	ENSP00000263208.5	25	MANE Select
ENST00000340170.8	Ensembl	ENSP00000345350.4	21	Standard
ENST00000340170.9	Ensembl	ENSP00000345350.4	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Formation of Senescence-Associated Heterochromatin Foci (SAHF)
DNA Damage/Telomere Stress Induced Senescence
Cellular Senescence
Cellular responses to stress
Cellular responses to external stimuli

Biological Process

mitotic sister chromatid segregation
osteoblast differentiation
DNA replication-independent nucleosome assembly
transcription, DNA-templated
regulation of transcription by RNA polymerase II

Molecular Function

DNA binding
DNA-binding transcription factor activity
transcription corepressor activity
protein binding
nucleosome binding

Cellular Component

HIR complex
chromosome, centromeric region
nuclear chromatin
nucleus
nucleoplasm

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000263208
Coding exons: 25
Length: 117004
Individuals with no LoFs: 125742
Homozygous LoFs: 0
Heterozygous LoFs: 5
Defined: 125747
p: 0.0000199

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.71	352	610	0.578	0.0000371	6603
Missense (PolyPhen)		86	234.29	0.36707		2454
Synonymous	-0.423	260	251	1.03	0.0000163	2058
Loss of Function	6.63	3	57.1	0.0526	0.00000303	619

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	0.000092	0.000092	rare
European (Non-Finnish)	0.000026	0.000026	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Cooperates with ASF1A to promote replication-independent chromatin assembly. Required for the periodic repression of histone gene transcription during the cell cycle. Required for the formation of senescence-associated heterochromatin foci (SAHF) and efficient senescence-associated cell cycle exit. {ECO:0000269|PubMed:12370293, ECO:0000269|PubMed:14718166, ECO:0000269|PubMed:15621527}.;

Recessive Scores

pRec: 0.232

Intolerance Scores

LoFtool: 0.0158
RVIS EVS: -1.37
RVIS percentile EVS: 4.43

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 1.00

Gene Damage Prediction

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