THBS1

protein-coding

thrombospondin 1, the group of Thrombospondin family

Gene summary

The protein encoded by this gene is a subunit of a disulfide-linked homotrimeric protein. This protein is an adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. This protein can bind to fibrinogen, fibronectin, laminin, type V collagen and integrins alpha-V/beta-1. This protein has been shown to play roles in platelet aggregation, angiogenesis, and tumorigenesis. [provided by RefSeq, Jul 2008]

MANE transcript

NM_003246.4

Inheritance

AR, AD

ClinVar variants

P:1U:128B:27

Top phenotype

congenital glaucoma

gnomAD constraint

pLI —, LoF o/e 0.13

Max pathogenic AF

—

Genomic locus

chr15:39,581,079-39,599,466

External References & Databases

Ensembl (ENSG00000137801)

Transcript & Mutation Effects

hg38 • Region Span ~18.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nonsyndromic genetic hearing lossLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: Ambry Genetics

congenital glaucomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0020366

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to THBS1 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 115

THBS1-related disorderTotal: 25

not providedTotal: 20

Premature ovarian failureTotal: 1

Autism spectrum disorderTotal: 1

Hearing impairmentTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003246.4. 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				15 clinvar	6 clinvar	21
missense		1 clinvar	122 clinvar	5 clinvar	1 clinvar	129
nonsense			1 clinvar			1
start loss						0
frameshift			2 clinvar			2
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	1	128	20	7	156

Highest pathogenic variant AF is 0.000091687194

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003246.4	RefSeq	NP_003237.2	21	MANE Select
ENST00000260356.6	Ensembl	ENSP00000260356.5	21	MANE Select
ENST00000397591.2	Ensembl	ENSP00000380720.2	2	Standard
ENST00000880750.1	Ensembl	ENSP00000550809.1	21	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

PI3K-Akt signaling pathway - Homo sapiens (human)
ECM-receptor interaction - Homo sapiens (human)
Focal adhesion - Homo sapiens (human)
TGF-beta signaling pathway - Homo sapiens (human)
Bladder cancer - Homo sapiens (human)

Biological Process

activation of MAPK activity
response to hypoxia
negative regulation of endothelial cell proliferation
negative regulation of cell-matrix adhesion
sprouting angiogenesis

Molecular Function

phosphatidylserine binding
fibronectin binding
integrin binding
extracellular matrix structural constituent
calcium ion binding

Cellular Component

extracellular region
fibrinogen complex
extracellular space
endoplasmic reticulum
endoplasmic reticulum lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000260356
Coding exons: 21
Length: 18388
Individuals with no LoFs: 125728
Homozygous LoFs: 0
Heterozygous LoFs: 20
Defined: 125748
p: 0.0000795

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.72	516	721	0.715	0.0000434	7833
Missense (PolyPhen)		181	316.89	0.57117		3482
Synonymous	1.70	248	284	0.872	0.0000186	2167
Loss of Function	6.06	7	56.0	0.125	0.00000273	624

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000071	0.000070	rare
South Asian	0.000034	0.000033	rare
Other	0.00020	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions. Binds heparin. May play a role in dentinogenesis and/or maintenance of dentin and dental pulp (By similarity). Ligand for CD36 mediating antiangiogenic properties. Plays a role in ER stress response, via its interaction with the activating transcription factor 6 alpha (ATF6) which produces adaptive ER stress response factors (By similarity). {ECO:0000250, ECO:0000269|PubMed:11134179, ECO:0000269|PubMed:15014436}.;

Recessive Scores

pRec: 0.935

Intolerance Scores

LoFtool: 0.104
RVIS EVS: -1.74
RVIS percentile EVS: 2.39

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.955

Gene Damage Prediction

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