Human Gene Module / Chromosome 15 / TRPM7

TRPM7transient receptor potential cation channel subfamily M member 7

SFARI Gene Score
3
Suggestive Evidence Criteria 3.1
Autism Reports / Total Reports
5 / 8
Rare Variants / Common Variants
12 / 0
Aliases
-
Associated Syndromes
-
Chromosome Band
15q21.2
Associated Disorders
-
Relevance to Autism

Bosman et al., 2024 reported de novo missense variants in the TRPM7 gene in three unrelated individuals presenting with hypomagnesemia, autism spectrum disorder, and developmental delay; all three missense variants were shown experimentally to result in loss-of-function of TRPM7-mediated magnesium uptake in transfected HEK293 cells with no effects on expression or plasma membrane insertion. Rare genetic variation in TRPM7 had previously been associated with hypomagnesemia with or without seizures (Lei et al., 2022; Vargas-Poussou et al., 2023). Rare de novo missense variants in TRPM7 have also been identified in three ASD probands from the Simons Simplex Collection, the Autism Sequencing Consortium, and the SPARK cohort (Iossifov et al., 2014; Satterstrom et al., 2020; Zhou et al., 2022), while de novo loss-of-function variants in this gene have been reported in two ASD probands (Zhou et al., 2022; Fu et al., 2022).

Molecular Function

This gene belongs to the melastatin subfamily of transient receptor potential family of ion channels. The protein encoded by this gene is both an ion channel and a serine/threonine protein kinase. The kinase activity is essential for the ion channel function, which serves to increase intracellular calcium levels and to help regulate magnesium ion homeostasis. The encoded protein is involved in cytoskeletal organization, cell adhesion, cell migration and organogenesis. A heterozygous missense variant in this gene that was shown experimentally to increase susceptibility to inhibition by intracellular magnesium concentrations compared to wildtype channels (p.Thr1482Ile) is a cause of amyotrophic lateral sclerosis-parkinsonism/dementia complex of Guam (Hermosura et al., 2005). The gene may also be associated with defects of cardiac function.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to TRPM7 (8 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support - Meredith C Hermosura et al. (2005) No -
2 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
3 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
4 Support - Rosa Vargas-Poussou et al. (2023) No DD, epilepsy/seizures
5 Support - Meifang Lei et al. (2022) No Hemiplegic migraines
6 Support - Zhou X et al. (2022) Yes -
7 Support - Fu JM et al. (2022) Yes -
8 Primary - Willem Bosman et al. (2024) Yes ADHD, epilepsy/seizures
Rare Variants   (12)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4732+5A>C - splice_site_variant De novo - - 35982159 Zhou X et al. (2022)
c.1495-6T>C - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.3575G>A p.Gly1192Glu missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2999T>C p.Met1000Thr missense_variant De novo - - 39099563 Willem Bosman et al. (2024)
c.3136G>C p.Gly1046Arg missense_variant De novo - - 39099563 Willem Bosman et al. (2024)
c.3242T>G p.Leu1081Arg missense_variant De novo - - 39099563 Willem Bosman et al. (2024)
c.2435T>A p.Met812Lys missense_variant De novo - - 31981491 Satterstrom FK et al. (2020)
c.1135A>G p.Thr379Ala missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2852_2853dup p.Ala952MetfsTer13 frameshift_variant De novo - - 35982160 Fu JM et al. (2022)
c.2998A>G p.Met1000Val missense_variant De novo - Simplex 35712613 Meifang Lei et al. (2022)
c.3137G>A p.Gly1046Asp missense_variant De novo - Simplex 35561741 Rosa Vargas-Poussou et al. (2023)
c.3+1G>C - splice_site_variant Familial Maternal Extended multiplex 35561741 Rosa Vargas-Poussou et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
3

Suggestive Evidence

criteria met
See SFARI Gene'scoring criteria
3

Suggestive Evidence

See all Category 3 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as "acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2024
3

Initial score established: 3

Krishnan Probability Score

Score 0.44639966305637

Ranking 14788/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 1.6555353762781E-8

Ranking 16095/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.92077233364365

Ranking 9248/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score -0.016430390620056

Ranking 9219/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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