TSPAN7

protein-coding

tetraspanin 7, the group of Tetraspanins|CD molecules

Gene summary

The protein encoded by this gene is a member of the transmembrane 4 superfamily, also known as the tetraspanin family. Most of these members are cell-surface proteins that are characterized by the presence of four hydrophobic domains. The proteins mediate signal transduction events that play a role in the regulation of cell development, activation, growth and motility. This encoded protein is a cell surface glycoprotein and may have a role in the control of neurite outgrowth. It is known to complex with integrins. This gene is associated with X-linked cognitive disability and neuropsychiatric diseases such as Huntington's chorea, fragile X syndrome and myotonic dystrophy. [provided by RefSeq, Jul 2008]

Previous symbols:

MXS1
TM4SF2
MRX58

MANE transcript

NM_004615.4

Inheritance

ClinVar variants

P:5U:87B:10

Top phenotype

Intellectual developmental disorder, X-linked 58

gnomAD constraint

pLI —, LoF o/e 0.11

Max pathogenic AF

—

Genomic locus

chrX:38,561,542-38,688,920

External References & Databases

Ensembl (ENSG00000156298)

Transcript & Mutation Effects

hg38 • Region Span ~127.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder, X-linked 58MODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0010266

Submitter: PanelApp Australia

non-syndromic X-linked intellectual disabilityMODERATE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: ClinGen

TSPAN7 was initially reported in relation to X-linked intellectual disability in 2000 (PMID: 10655063). A female with mild intellectual disability was found to carry a balanced translocation [46,X,t(X;2)(p11.4;p21.3)] with a breakpoint within TSPAN7 that disrupted its expression. Though this case was not scored, it ultimately led to further investigation of this gene as a potential cause for X-linked intellectual disability (PMID: 10655063). One family with multiple affected males was found to have a nonsense variant. Another family was found to have a missense variant (NM_004615.3:c.515C>A, p.Pro172His); this variant was also reported in other manuscripts as being observed in individuals with intellectual disability or autism spectrum disorder (PMIDs: 14735593, 20479760). This variant was subsequently found to be observed at frequencies too high in the general population to be consistent with disease (205 total alleles across various populations in gnomAD v.2.1.1, including 66 hemizygotes), and was therefore not scored as evidence to support this gene disease relationship. Since the initial report, only two other frameshift variants have been reported: one in four affected males in a family with X-linked intellectual disability (PMID: 12070254), and the other in a male with intellectual disability (PMID: 26350204). Other articles reported individuals with intellectual disability or autism spectrum disorder with a partial duplication of TSPAN7 spanning exons 2-8 (PMID: 22511893, 19339915, 24768552, 25661985). This recurrent duplication is of uncertain significance and was therefore not scored. There is experimental evidence to support this gene-disease relationship, including functional alteration in hippocampal neurons (PMID:22445342) and a mouse model (PMID:28968657). In summary, there is moderate evidence supporting a relationship between TSPAN7 and X-linked intellectual disability. This curation was approved by the ClinGen ID/Autism GCEP on December 2, 2020 (SOP v8).

intellectual developmental disorder, X-linked 58STRONG

Inheritance Pattern: XL

Disease ID:MONDO:0010266

Submitter: Labcorp Genetics (formerly Invitae)

non-syndromic X-linked intellectual disabilitySUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0019181

Submitter: Orphanet

intellectual developmental disorder, X-linked 58DEFINITIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010266

Submitter: G2P

Clinical Genomic Database (CGD)

Intellectual developmental disorder, X-linked 58XL

Manifestation: Neurologic

Intervention: General

Rationale: 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

Refs: 10449641; 10655063; 14735593

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to TSPAN7 variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 29

not providedTotal: 17

Intellectual disability, X-linked 58Total: 10

TSPAN7-related disorderTotal: 6

Intellectual disabilityTotal: 2

History of neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004615.4. 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			11 clinvar	5 clinvar	2 clinvar	18
missense			53 clinvar	3 clinvar		56
nonsense	2 clinvar		7 clinvar			9
start loss						0
frameshift	2 clinvar		1 clinvar			3
splice donor/acceptor (+/-2bp)		1 clinvar	15 clinvar			16
Total	4	1	87	8	2	102

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004615.4	RefSeq	NP_004606.2	7	MANE Select
ENST00000378482.7	Ensembl	ENSP00000367743.2	7	MANE Select
ENST00000286824.6	Ensembl	ENSP00000286824.6	8	Standard
ENST00000286824.7	Ensembl	ENSP00000286824.6	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Transcriptional misregulation in cancer - Homo sapiens (human)
Neuronal System
Cell surface interactions at the vascular wall
Hemostasis
Trafficking of GluR2-containing AMPA receptors

Biological Process

cell surface receptor signaling pathway
viral process

Cellular Component

integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378482
Coding exons: 7
Length: 127547
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.91	48	102	0.470	0.00000796	1622
Missense (PolyPhen)		2	23.027	0.086853		411
Synonymous	-0.180	43	41.5	1.04	0.00000343	496
Loss of Function	2.45	1	8.86	0.113	6.45e-7	145

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in cell proliferation and cell motility.;

Recessive Scores

pRec: 0.171

Intolerance Scores

RVIS EVS: -0.08
RVIS percentile EVS: 47.79

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.233

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Low	Low	Low
Primary Immunodeficiency	Low	Low	Low
Cancer	Low	Low	Low