ITIH1

protein-coding

inter-alpha-trypsin inhibitor heavy chain 1, the group of Inter-alpha-trypsin inhibitor heavy chains

Gene summary

This gene encodes a member of the inter-alpha-trypsin inhibitor family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the heavy chain of the inter-alpha-trypsin inhibitor complex, which is secreted by hepatocytes into the blood. The heavy chain also interacts with hyaluronan, and this interaction may play a role in ovulation and fertilization, and has been implicated in multiple inflammatory diseases. This gene is present in a gene cluster on chromosome 3. [provided by RefSeq, Nov 2015]

MANE transcript

NM_002215.4

Inheritance

—

ClinVar variants

U:151B:13

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.97

Max pathogenic AF

—

Genomic locus

chr3:52,777,595-52,792,068

External References & Databases

Ensembl (ENSG00000055957)

Transcript & Mutation Effects

hg38 • Region Span ~14.5 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 ITIH1 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 159

not providedTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002215.4. 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				2 clinvar	1 clinvar	3
missense			150 clinvar	9 clinvar	1 clinvar	160
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	151	11	2	164

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002215.4	RefSeq	NP_002206.2	22	MANE Select
ENST00000273283.7	Ensembl	ENSP00000273283.2	22	MANE Select
NM_001166434.3	RefSeq	NP_001159906.1	18	Standard
NM_001166435.2	RefSeq	NP_001159907.1	15	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of endopeptidase activity
hyaluronan metabolic process

Molecular Function

serine-type endopeptidase inhibitor activity
calcium ion binding

Cellular Component

extracellular region
collagen-containing extracellular matrix
extracellular exosome
blood microparticle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000273283
Coding exons: 22
Length: 14476
Individuals with no LoFs: 125108
Homozygous LoFs: 5
Heterozygous LoFs: 635
Defined: 125748
p: 0.00255

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.285	531	550	0.966	0.0000332	5980
Missense (PolyPhen)		195	192.11	1.015		2241
Synonymous	0.591	214	225	0.950	0.0000146	1771
Loss of Function	0.216	48	49.6	0.967	0.00000271	513

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0011	notable
Latino/Admixed American	0.0025	0.0024	notable
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.0019	0.0019	notable
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.0011	0.00099	notable
South Asian	0.012	0.012	notable
Other	0.0024	0.0023	notable

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: 0.156

Intolerance Scores

LoFtool: 0.385
RVIS EVS: -0.83
RVIS percentile EVS: 11.53

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.152

Gene Damage Prediction

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