TIMP3

TIMP metallopeptidase inhibitor 3, the group of Tissue inhibitor of metallopeptidases

Basic information

Region (hg38): 22:32801704-32863041

Previous symbols: [ "SFD" ]

Links

ENSG00000100234 ∙ NCBI:7078 ∙ OMIM:188826 ∙ HGNC:11822 ∙ Uniprot:P35625 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Sorsby fundus dystrophy (Strong), mode of inheritance: AD
• Sorsby fundus dystrophy (Supportive), mode of inheritance: AD
• Sorsby fundus dystrophy (Definitive), mode of inheritance: AD
• Sorsby fundus dystrophy (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Sorsby fundus dystrophy	AD	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	Ophthalmologic	18111349; 7148944; 7894485; 7550309; 8981947; 18501328
Vitamin A administration in early disease stages may postively affect manifestations such as night blindness, but long term efficacy is unclear; Antioangiogenic agents have been suggested as possibly beneficial

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the TIMP3 gene.

• not provided (3 variants)
• Sorsby fundus dystrophy (2 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the TIMP3 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			1	39	3	43
missense	3	3	60	1	2	69
nonsense			4			4
start loss						0
frameshift			1			1
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region			3	2		5
non coding			59	18	31	108
Total	3	3	126	58	36

Variants in TIMP3

This is a list of pathogenic ClinVar variants found in the TIMP3 region.

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

Position	Type	Phenotype	Significance	ClinVar
22-32801718-G-C		Sorsby fundus dystrophy	Uncertain significance (Jan 12, 2018)
22-32801728-G-C		Sorsby fundus dystrophy	Uncertain significance (Apr 27, 2017)
22-32801732-G-T		Sorsby fundus dystrophy	Uncertain significance (Jan 13, 2018)
22-32801885-G-A		Sorsby fundus dystrophy	Benign (Jan 13, 2018)
22-32801897-G-C		Sorsby fundus dystrophy	Uncertain significance (Jan 13, 2018)
22-32802008-C-T			Uncertain significance (Jul 17, 2023)
22-32802012-G-C			Uncertain significance (Feb 16, 2023)
22-32802014-C-T			Uncertain significance (Oct 04, 2022)
22-32802016-C-T			Likely benign (Jan 04, 2024)
22-32802022-C-T			Likely benign (Nov 04, 2022)
22-32802025-C-A			Likely benign (Nov 15, 2022)
22-32802026-G-A			Uncertain significance (Jul 07, 2023)
22-32802029-C-T			Uncertain significance (Nov 01, 2022)
22-32802030-T-A			Uncertain significance (May 23, 2020)
22-32802035-G-C		Retinal dystrophy	Conflicting classifications of pathogenicity (Nov 06, 2023)
22-32802045-G-T			Uncertain significance (Jun 07, 2022)
22-32802046-C-T			Likely benign (Oct 09, 2020)
22-32802048-T-C		not specified	Uncertain significance (Jan 22, 2024)
22-32802052-G-T			Benign/Likely benign (Nov 01, 2022)
22-32802053-G-T			Uncertain significance (Aug 18, 2021)
22-32802054-A-G			Uncertain significance (Mar 01, 2023)
22-32802065-G-C			Benign (Oct 30, 2023)
22-32802071-T-C			Uncertain significance (May 30, 2023)
22-32802071-T-G			Uncertain significance (Aug 07, 2023)
22-32802072-G-T			Uncertain significance (Sep 30, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
TIMP3	protein_coding	protein_coding	ENST00000266085	5	61344

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.630	0.368	125727	0	2	125729	0.00000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.83	68	126	0.541	0.00000760	1373
Missense in Polyphen		14	53.44	0.26198		531
Synonymous	-0.133	53	51.8	1.02	0.00000327	389
Loss of Function	2.64	2	11.8	0.169	5.97e-7	130

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000177	0.0000176
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor. May form part of a tissue-specific acute response to remodeling stimuli. Known to act on MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-13, MMP-14 and MMP-15.
• Disease: DISEASE: Sorsby fundus dystrophy (SFD) [MIM:136900]: Rare autosomal dominant macular disorder with an age of onset in the fourth decade. It is characterized by loss of central vision from subretinal neovascularization and atrophy of the ocular tissues. Generally, macular disciform degeneration develops in the patients eye within 6 months to 6 years. {ECO:0000269|PubMed:7550309, ECO:0000269|PubMed:7894485, ECO:0000269|PubMed:8634721, ECO:0000269|PubMed:8728699, ECO:0000269|PubMed:8981947}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Proteoglycans in cancer - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);VEGF Signaling Pathway;Matrix Metalloproteinases;Angiogenesis;Oncostatin M Signaling Pathway;Vitamin D Receptor Pathway;Protein alkylation leading to liver fibrosis;Endochondral Ossification;inhibition of matrix metalloproteinases;Platelet degranulation ;Response to elevated platelet cytosolic Ca2+;Platelet activation, signaling and aggregation;p53 signaling pathway;Hemostasis (Consensus)

Intolerance Scores

• loftool: 0.281
• rvis_EVS: -0.14
• rvis_percentile_EVS: 42.88

Haploinsufficiency Scores

• pHI: 0.309
• hipred: Y
• hipred_score: 0.555
• ghis: 0.552

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.743

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Timp3
• Phenotype: vision/eye phenotype; renal/urinary system phenotype; immune system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; liver/biliary system phenotype; pigmentation phenotype; endocrine/exocrine gland phenotype; growth/size/body region 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); hematopoietic system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan)

Gene ontology

• Biological process: platelet degranulation;visual perception;response to hormone;response to organic substance;negative regulation of endopeptidase activity;response to cytokine;negative regulation of membrane protein ectodomain proteolysis;negative regulation of ERK1 and ERK2 cascade;cellular response to organic substance;positive regulation of TRAIL-activated apoptotic signaling pathway;negative regulation of metalloendopeptidase activity
• Cellular component: extracellular region;basement membrane;extracellular space;nucleus;extracellular matrix;platelet dense granule lumen;collagen-containing extracellular matrix
• Molecular function: protease binding;protein binding;metalloendopeptidase inhibitor activity;metal ion binding