HTRA1

HtrA serine peptidase 1, the group of Serine proteases|PDZ domain containing

Basic information

Region (hg38): 10:122458550-122514907

Previous symbols: [ "PRSS11" ]

Links

ENSG00000166033 ∙ NCBI:5654 ∙ OMIM:602194 ∙ HGNC:9476 ∙ Uniprot:Q92743 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• genetic cerebral small vessel disease (Strong), mode of inheritance: AD
• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 (Strong), mode of inheritance: AD
• CARASIL syndrome (Strong), mode of inheritance: AR
• CARASIL syndrome (Supportive), mode of inheritance: AR
• HTRA1-related autosomal dominant cerebral small vessel disease (Supportive), mode of inheritance: AD
• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 (Strong), mode of inheritance: AD
• CARASIL syndrome (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 2 (CADASIL2); Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL)	AD/AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Cardiovascular; Dermatologic; Neurologic	17053108; 17053109; 17884985; 17568988; 18511946; 19387015; 20437615; 21115960; 21482952; 22900900; 24500651; 26063658

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the HTRA1 gene.

• not provided (193 variants)
• Macular degeneration (39 variants)
• Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 (24 variants)
• CARASIL syndrome (19 variants)
• not specified (10 variants)
• Inborn genetic diseases (10 variants)
• HTRA1-related condition (5 variants)
• Vascular dementia (2 variants)
• HTRA1-related cerebral small vessel disease (2 variants)
• CARASIL syndrome;Age related macular degeneration 7;Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 2 (1 variants)
• Small vessel cerebrovascular disease (1 variants)
• Cognitive impairment;Seizure;Personality changes (1 variants)
• HTRA1-related autosomal dominant cerebral small vessel disease (1 variants)
• See cases (1 variants)
• Age related macular degeneration 7 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the HTRA1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			3	40	2	45
missense	4	9	89	5	1	108
nonsense	1	5	1			7
start loss						0
frameshift	4	2	2			8
inframe indel			4			4
splice donor/acceptor (+/-2bp)		3				3
splice region			4	3	2	9
non coding			5	7	20	32
Total	9	19	104	52	23

Highest pathogenic variant AF is 0.0000263

Variants in HTRA1

This is a list of pathogenic ClinVar variants found in the HTRA1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
10-122458639-AG-A			Uncertain significance (Aug 01, 2021)
10-122461028-G-A		Age related macular degeneration 7 • Susceptibility to neovascular type of age-related macular degeneration	risk factor (Feb 18, 2015)
10-122461596-C-A		Macular degeneration	Likely benign (Jun 14, 2016)
10-122461660-T-A			Uncertain significance (May 17, 2023)
10-122461661-C-A			Likely benign (Jan 02, 2024)
10-122461662-C-T		Macular degeneration	Uncertain significance (Jan 12, 2018)
10-122461664-G-T		Macular degeneration	Conflicting classifications of pathogenicity (Dec 11, 2023)
10-122461667-C-G			Likely benign (Aug 09, 2022)
10-122461672-C-G		Inborn genetic diseases	Uncertain significance (Mar 30, 2023)
10-122461679-C-G		HTRA1-related disorder	Likely benign (Jun 16, 2022)
10-122461681-C-CGCT			Uncertain significance (Nov 17, 2023)
10-122461686-C-T		Macular degeneration	Conflicting classifications of pathogenicity (Oct 13, 2023)
10-122461685-G-GTCC		Macular degeneration	Conflicting classifications of pathogenicity (Oct 13, 2023)
10-122461686-C-TCCT			Uncertain significance (Aug 11, 2023)
10-122461711-C-T		Macular degeneration • CARASIL syndrome • not specified	Benign/Likely benign (Jan 25, 2024)
10-122461714-C-T		Inborn genetic diseases	Uncertain significance (Feb 28, 2024)
10-122461722-C-T			Likely benign (Oct 08, 2023)
10-122461725-T-C			Uncertain significance (Aug 19, 2023)
10-122461726-C-T			Uncertain significance (Mar 03, 2023)
10-122461728-C-T		Inborn genetic diseases	Uncertain significance (Dec 28, 2023)
10-122461729-G-A		Macular degeneration	Benign/Likely benign (Jan 24, 2024)
10-122461736-C-A			Likely benign (Nov 01, 2022)
10-122461744-C-A			Uncertain significance (Jan 09, 2024)
10-122461744-C-T			Uncertain significance (Sep 07, 2023)
10-122461748-T-G			Likely benign (Dec 31, 2019)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
HTRA1	protein_coding	protein_coding	ENST00000368984	9	53384

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000492	0.994	125732	0	16	125748	0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.05	195	241	0.809	0.0000164	3042
Missense in Polyphen		78	114.97	0.67843		1293
Synonymous	-0.510	109	102	1.06	0.00000798	1010
Loss of Function	2.41	9	20.9	0.431	0.00000146	225

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000578	0.0000578
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.0000924	0.0000924
European (Non-Finnish)	0.0000528	0.0000527
Middle Eastern	0.000163	0.000163
South Asian	0.0000653	0.0000653
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Serine protease with a variety of targets, including extracellular matrix proteins such as fibronectin. HTRA1-generated fibronectin fragments further induce synovial cells to up-regulate MMP1 and MMP3 production. May also degrade proteoglycans, such as aggrecan, decorin and fibromodulin. Through cleavage of proteoglycans, may release soluble FGF-glycosaminoglycan complexes that promote the range and intensity of FGF signals in the extracellular space. Regulates the availability of insulin-like growth factors (IGFs) by cleaving IGF-binding proteins. Inhibits signaling mediated by TGF-beta family members. This activity requires the integrity of the catalytic site, although it is unclear whether TGF-beta proteins are themselves degraded. By acting on TGF-beta signaling, may regulate many physiological processes, including retinal angiogenesis and neuronal survival and maturation during development. Intracellularly, degrades TSC2, leading to the activation of TSC2 downstream targets. {ECO:0000269|PubMed:16377621, ECO:0000269|PubMed:20671064, ECO:0000269|PubMed:9852107}.
• Disease: DISEASE: Macular degeneration, age-related, 7 (ARMD7) [MIM:610149]: A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. {ECO:0000269|PubMed:17053108, ECO:0000269|PubMed:17053109}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy (CARASIL) [MIM:600142]: A cerebrovascular disease characterized by non- hypertensive arteriopathy of cerebral small vessels with subcortical infarcts, alopecia, and spondylosis. Small cerebral arteries show arteriosclerotic changes, fibrous intimal proliferation, and hyaline degeneration with splitting of the intima and/or the internal elastic membrane. Neurologic features include progressive dementia, gait disturbances, extrapyramidal and pyramidal signs, and demyelination of the cerebral white matter with sparing of U fibers. {ECO:0000269|PubMed:19387015}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, 2 (CADASIL2) [MIM:616779]: A cerebrovascular disease characterized by multiple subcortical infarcts, pseudobulbar palsy, dementia, and the presence of granular deposits in small cerebral arteries producing ischemic stroke. {ECO:0000269|PubMed:26063658}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Extracellular matrix organization;Degradation of the extracellular matrix (Consensus)

Recessive Scores

• pRec: 0.332

Haploinsufficiency Scores

• pHI: 0.330
• hipred: Y
• hipred_score: 0.563
• ghis: 0.630

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.326

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Htra1
• Phenotype: skeleton phenotype; vision/eye phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan)

Zebrafish Information Network

• Gene name: htra1a
• Affected structure: caudal fin lower lobe
• Phenotype tag: abnormal
• Phenotype quality: absent

Gene ontology

• Biological process: regulation of cell growth;placenta development;proteolysis;extracellular matrix disassembly;negative regulation of transforming growth factor beta receptor signaling pathway;negative regulation of BMP signaling pathway;positive regulation of epithelial cell proliferation;negative regulation of defense response to virus;chorionic trophoblast cell differentiation;dentinogenesis
• Cellular component: extracellular region;extracellular space;cytosol;plasma membrane;collagen-containing extracellular matrix;extracellular exosome
• Molecular function: serine-type endopeptidase activity;protein binding;insulin-like growth factor binding;serine-type peptidase activity;identical protein binding