ITIH4

protein-coding

inter-alpha-trypsin inhibitor heavy chain 4, the group of Inter-alpha-trypsin inhibitor heavy chains

Gene summary

The protein encoded by this gene is secreted into the blood, where it is cleaved by plasma kallikrein into two smaller forms. Expression of this gene has been detected only in liver, and it seems to be upregulated during surgical trauma. This gene is part of a cluster of similar genes on chromosome 3. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

Previous symbols:

ITIHL1

MANE transcript

NM_002218.5

Inheritance

—

ClinVar variants

U:120B:30

Top phenotype

ITIH4-related disorder

gnomAD constraint

pLI —, LoF o/e 0.56

Max pathogenic AF

—

Genomic locus

chr3:52,812,962-52,830,688

External References & Databases

Ensembl (ENSG00000055955)

Transcript & Mutation Effects

hg38 • Region Span ~17.7 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 ITIH4 variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 122

not providedTotal: 10

ITIH4-related disorderTotal: 10

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002218.5. 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	6 clinvar	5 clinvar	12
missense			115 clinvar	16 clinvar	3 clinvar	134
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	120	22	8	150

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 161 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_002218.5	RefSeq	NP_002209.2	24	MANE Select
ENST00000266041.9	Ensembl	ENSP00000266041.4	24	MANE Select
NM_001166449.2	RefSeq	NP_001159921.1	22	Standard
ENST00000406595.5	Ensembl	ENSP00000384425.1	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
acute-phase response
negative regulation of endopeptidase activity
hyaluronan metabolic process
response to cytokine

Molecular Function

endopeptidase inhibitor activity
serine-type endopeptidase inhibitor activity
protein binding

Cellular Component

extracellular region
plasma membrane
platelet dense granule lumen
collagen-containing extracellular matrix
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000266041
Coding exons: 24
Length: 18505
Individuals with no LoFs: 125667
Homozygous LoFs: 0
Heterozygous LoFs: 81
Defined: 125748
p: 0.000322

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.27	478	563	0.849	0.0000337	6042
Missense (PolyPhen)		157	208.31	0.75369		2455
Synonymous	0.263	223	228	0.978	0.0000140	1871
Loss of Function	2.88	28	50.0	0.560	0.00000247	542

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00068	0.00068	rare
Latino/Admixed American	0.00036	0.00035	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00060	0.00044	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00031	0.00031	rare
South Asian	0.00064	0.00046	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Type II acute-phase protein (APP) involved in inflammatory responses to trauma. May also play a role in liver development or regeneration. {ECO:0000269|PubMed:19263524}.;

Recessive Scores

pRec: 0.306

Intolerance Scores

LoFtool: 0.772
RVIS EVS: -0.43
RVIS percentile EVS: 24.72

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0994

Gene Damage Prediction

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