TSPAN7

Gene Facts

• HGNC Symbol: TSPAN7 (HGNC:11854)
• HGNC Name: tetraspanin 7
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: MXS1, TM4SF2, MRX58
• Alias symbols: DXS1692E, TALLA-1, A15, CD231
• %HI: 17.96
• pLI: 0.75
• LOEUF: 0.54
• Cytoband: Xp11.4
• Genomic Coordinates:

  GRCh37/hg19:	chrX:38420795-38548172
  GRCh38/hg38:	chrX:38561542-38688918

• MANE Select Transcript: NM_004615.4 ENST00000378482.7
• Function: May be involved in cell proliferation and cell motility. (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-34139
• ClinGen Curation ID: CCID:008056
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Little Evidence for Haploinsufficiency (1)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 06/22/2022

Haploinsufficiency (HI) Score Details

• HI Score: 1
• HI Evidence Strength: Little Evidence for Haploinsufficiency

HI Disease

• X-linked intellectual disability

HI Evidence

• PUBMED: 12070254
  Abidi et al. (2002) provide a follow up report on a family originally reported by Holinski-Feder et al (PMID: 10449641) in which a frameshift variant, p.(Val191Glyfs*6), segregates with non-syndromic intellectual disability in 5 males. Two carrier females had normal intelligence.
• PUBMED: 10655063
  Zemni et al. (2000, PMID: 10655063) report a female with intellectual disability and minor autistic features who had an apparently balanced t(X;2)(p11.4;p21.3) that disrupted TSPAN7. RT-PCR barely detected any transcripts. The authors also report a family with four males with non-syndromic intellectual disability and a nonsense mutation. This mutation is near the 3' end of the gene and RT-PCR showed normal transcription levels. The resulting protein lacks the fourth transmembrane segment and the carboxy-terminal domain. Additional clinical details on this family are provided in De Vos et al, PMID:12150222. Additionally, a missense mutation (P172H) was found in another family with X-linked intellectual disability. This family is further described by Gomot et al., PMID: 12376945. We are not counting the nonsense mutation as evidence from this report due to the normal transcription levels. We did not count the translocation since they did not map the breakpoint on chromosome 2 to show that there is no gene involved from that breakpoint.
• PUBMED: 26350204
  Grozeva et al (2015) performed targeted NGS of 565 intellectual disability (ID)-associated genes on individuals with ID. Multiple TSPAN7 variants were identified, including missense changes and one frameshift. The frameshift change occurred in exon 2 of 8 (NM_004615) and was identified in a male.

• HI Evidence Comments: Of note: Two additional patients have been reported with the P172H mutation first described by Zemni et al. Piton et al. (2011) found this mutation in a male with autism and his unaffected mother (PMID: 20479760). Maranduba et al. (2004) reported this mutation in a male with intellectual disability, dysmorphic features, nystagmus, and myopia. It was found in his normal sister and mother but not in his normal brother (PMID: 14735593). Functional studies have not been reported in any of the individuals with this mutation. Blue et al (2022; PMID: 34670123) in Am. Heart Journal reports a missense variant, p.(Pro172His), previously thought to cause X-linked ID. This missense variant was initially classified as pathogenic by some of the original publications (e.g PMID 14735593 Maranduba (2004) Am J Med Genet and also the Zemni et al 2000) The recurrent frequency of this missense variant in gnomAD, including in 66 males, is suggestive of this being a likely benign to uncertain category. Furthermore, the patient described in this study (PMID: 34670123) with this variant had normal Bayley Scale of Infant and Toddler Development-III (BSID-III).assessments. The missense change has conflicting interpretations in ClinVar (see Table in this publication; PMID: 34670123). Additionally 2 cases were reported in a large exome study (supp Table 1, PMID 31019283 ) in which TSPAN7 was found to have the same missense variant described above and they went onto classify it as uncertain. No functional studies have been performed. Partial duplications involving exons 2-8 have been reported in male patients with intellectual disability and/or autism, and their unaffected mothers, PMIDs: 22511893,19339915. However, a similar duplication is listed in DGV as a variant because it was found in controls (PMID:17638019). Furthermore, Cai et al. (2008, PMID:18925931) reported finding a similar duplication a girl with broad spectrum autistic features, her normal sister and mother, but not in her autistic brother. In another family in this paper, a similar duplication was found in a brother and sister with autism, as well as their healthy mother. This group also found the duplication in 2 male and 4 female ethnicity-matched controls and concluded that it was not likely to be pathogenic.

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity

NOTE

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.