HTRA4

protein-coding

HtrA serine peptidase 4, the group of PDZ domain containing

Gene summary

This gene encodes a member of the HtrA family of proteases. The encoded protein contains a putative signal peptide, an insulin growth factor binding domain, a Kazal protease inhibitor domain, a conserved trypsin domain and a PDZ domain. Based on studies on other related family members, this enzyme may function as a secreted oligomeric chaperone protease to degrade misfolded secretory proteins. Other human HtrA proteins have been implicated in arthritis, tumor suppression, unfolded stress response, apoptosis, and aging. [provided by RefSeq, Oct 2008]

MANE transcript

NM_153692.4

Inheritance

—

ClinVar variants

U:67B:4

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 0.91

Max pathogenic AF

—

Genomic locus

chr8:38,974,228-38,988,663

External References & Databases

Ensembl (ENSG00000169495)

Transcript & Mutation Effects

hg38 • Region Span ~14.4 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 HTRA4 variants in ClinVar

1 Conditions Cataloged

not specifiedTotal: 69

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_153692.4. 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						0
missense			65 clinvar	4 clinvar		69
nonsense			1 clinvar			1
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	67	4	0	71

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 5 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_153692.4	RefSeq	NP_710159.1	9	MANE Select
ENST00000302495.5	Ensembl	ENSP00000305919.4	9	MANE Select
ENST00001133409.1	Ensembl	ENSP00000805799.1	9	Standard
XM_011544431.3	RefSeq	XP_011542733.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

regulation of cell growth
proteolysis
negative regulation of transforming growth factor beta receptor signaling pathway

Molecular Function

endopeptidase activity
serine-type endopeptidase activity
insulin-like growth factor binding

Cellular Component

extracellular region

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000302495
Coding exons: 9
Length: 14499
Individuals with no LoFs: 124963
Homozygous LoFs: 4
Heterozygous LoFs: 781
Defined: 125748
p: 0.00313

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.968	206	249	0.827	0.0000136	3003
Missense (PolyPhen)		73	92.304	0.79086		1194
Synonymous	1.10	92	106	0.865	0.00000642	1011
Loss of Function	0.372	19	20.8	0.912	0.00000121	230

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0047	0.0047	notable
Latino/Admixed American	0.00087	0.00087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00060	0.00060	rare
Finnish	0.012	0.012	notable
European (Non-Finnish)	0.0035	0.0035	notable
South Asian	0.00036	0.00036	rare
Other	0.0028	0.0028	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine protease. {ECO:0000305}.;

Recessive Scores

pRec: 0.0719

Intolerance Scores

LoFtool: 0.399
RVIS EVS: 0.6
RVIS percentile EVS: 82.66

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.0793

Gene Damage Prediction

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