ITIH3

protein-coding

inter-alpha-trypsin inhibitor heavy chain 3, the group of Inter-alpha-trypsin inhibitor heavy chains

Gene summary

This gene encodes the heavy chain subunit of the pre-alpha-trypsin inhibitor complex. This complex may stabilize the extracellular matrix through its ability to bind hyaluronic acid. Polymorphisms of this gene may be associated with increased risk for schizophrenia and major depressive disorder. This gene is present in an inter-alpha-trypsin inhibitor family gene cluster on chromosome 3. [provided by RefSeq, Jul 2015]

MANE transcript

NM_002217.4

Inheritance

—

ClinVar variants

U:137B:8

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr3:52,794,768-52,808,799

External References & Databases

Ensembl (ENSG00000162267)

Transcript & Mutation Effects

hg38 • Region Span ~14.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ITIH3 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 137

not providedTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002217.4. 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			1 clinvar	1 clinvar	3 clinvar	5
missense			136 clinvar	2 clinvar	2 clinvar	140
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	137	3	5	145

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 23 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002217.4	RefSeq	NP_002208.3	22	MANE Select
ENST00000449956.3	Ensembl	ENSP00000415769.2	22	MANE Select
NM_001392019.1	RefSeq	NP_001378948.1	23	Standard
NM_001392020.1	RefSeq	NP_001378949.1	22	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Platelet degranulation
Response to elevated platelet cytosolic Ca2+
Platelet activation, signaling and aggregation
Hemostasis

Biological Process

platelet degranulation
negative regulation of endopeptidase activity
hyaluronan metabolic process

Molecular Function

endopeptidase inhibitor activity
serine-type endopeptidase inhibitor activity

Cellular Component

extracellular region
platelet dense granule lumen
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000449956
Coding exons: 22
Length: 14242
Individuals with no LoFs: 124994
Homozygous LoFs: 0
Heterozygous LoFs: 133
Defined: 125127
p: 0.000532

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.836	465	519	0.897	0.0000300	5849
Missense (PolyPhen)		136	150.65	0.90274		1801
Synonymous	-0.208	218	214	1.02	0.0000141	1656
Loss of Function	2.12	27	41.8	0.646	0.00000186	517

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00045	0.00044	rare
Latino/Admixed American	0.00089	0.00087	rare
Ashkenazi Jewish	0.00080	0.00079	rare
East Asian	0.00034	0.00033	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00045	0.00042	rare
South Asian	0.00092	0.00088	rare
Other	0.00072	0.00066	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May act as a carrier of hyaluronan in serum or as a binding protein between hyaluronan and other matrix protein, including those on cell surfaces in tissues to regulate the localization, synthesis and degradation of hyaluronan which are essential to cells undergoing biological processes.;

Recessive Scores

pRec: 0.116

Intolerance Scores

LoFtool: 0.673
RVIS EVS: 0.99
RVIS percentile EVS: 90.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.163

Gene Damage Prediction

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