TRPM3transient receptor potential cation channel subfamily M member 3
Autism Reports / Total Reports
5 / 14Rare Variants / Common Variants
24 / 0Aliases
-Associated Syndromes
-Chromosome Band
9q21.12Associated Disorders
-Relevance to Autism
A number of de novo variants in the TRPM3 gene, including a frameshift variant and a potentially damaging missense variant, have been observed in ASD probands (Iossifov et al., 2014; Satterstrom et al., 2020; Zhou et al., 2022). De novo gain-of-function variants in TRPM3 have been shown to cause a form of developmental and epileptic encephalopathy characterized by global developmental delay and intellectual disability, epilepsy, hypotonia, altered heat and/or pain sensitivity, and variable facial dysmorphism; a subset of affected individuals have been reported to also present with autism spectrum disorder, autistic features, and/or stereotypy (Dyment et al., 2019; de Sainte Agathe et al., 2020; Kang et al., 2021; Gauthier et al., 2021; Lines et al., 2022; Burglen et al., 2023).
Molecular Function
The product of this gene belongs to the family of transient receptor potential (TRP) channels. TRP channels are cation-selective channels important for cellular calcium signaling and homeostasis. The protein encoded by this gene mediates calcium entry, and this entry is potentiated by calcium store depletion.
External Links
SFARI Genomic Platforms
Reports related to TRPM3 (14 Reports)
| # | Type | Title | Author, Year | Autism Report | Associated Disorders |
|---|---|---|---|---|---|
| 1 | Support | The contribution of de novo coding mutations to autism spectrum disorder | Iossifov I et al. (2014) | Yes | - |
| 2 | Primary | - | Dyment DA et al. (2019) | No | Autistic features |
| 3 | Support | Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks | Ruzzo EK , et al. (2019) | Yes | - |
| 4 | Support | Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism | Satterstrom FK et al. (2020) | Yes | - |
| 5 | Support | - | Zhao S et al. (2020) | No | - |
| 6 | Support | - | Van Hoeymissen E et al. (2020) | No | - |
| 7 | Support | - | de Sainte Agathe JM et al. (2020) | No | Stereotypy |
| 8 | Support | - | Kang Q et al. (2021) | No | - |
| 9 | Support | - | Gauthier LW et al. (2021) | No | Autistic features, stereotypy |
| 10 | Support | - | Lines MA et al. (2022) | No | ID, epilepsy/seizures, autistic features, stereoty |
| 11 | Support | - | Zhou X et al. (2022) | Yes | - |
| 12 | Recent Recommendation | - | Burglen L et al. (2023) | No | ASD or autistic features, stereotypy |
| 13 | Support | - | Spataro N et al. (2023) | No | - |
| 14 | Support | - | Cirnigliaro M et al. (2023) | Yes | - |
Rare Variants (24)
| Status | Allele Change | Residue Change | Variant Type | Inheritance Pattern | Parental Transmission | Family Type | PubMed ID | Author, Year |
|---|---|---|---|---|---|---|---|---|
| c.839G>A | p.Ser280Asn | missense_variant | De novo | - | - | 35982159 | Zhou X et al. (2022) | |
| c.1272+121C>G | - | intron_variant | De novo | - | - | 31981491 | Satterstrom FK et al. (2020) | |
| c.1272+129A>G | - | intron_variant | De novo | - | - | 31981491 | Satterstrom FK et al. (2020) | |
| c.-24T>G | - | 5_prime_UTR_variant | De novo | - | - | 31981491 | Satterstrom FK et al. (2020) | |
| c.2968G>A | p.Val990Met | missense_variant | De novo | - | - | 35146895 | Lines MA et al. (2022) | |
| c.2305C>G | p.Leu769Val | missense_variant | De novo | - | - | 36648066 | Burglen L et al. (2023) | |
| c.2968G>A | p.Val990Met | missense_variant | De novo | - | - | 36980980 | Spataro N et al. (2023) | |
| c.3019G>A | p.Gly1007Ser | missense_variant | De novo | - | - | 36648066 | Burglen L et al. (2023) | |
| c.3376A>G | p.Asn1126Asp | missense_variant | De novo | - | - | 36648066 | Burglen L et al. (2023) | |
| c.3187+20T>C | - | intron_variant | De novo | - | Simplex | 31981491 | Satterstrom FK et al. (2020) | |
| c.3605G>C | p.Trp1202Ser | missense_variant | De novo | - | Simplex | 34074259 | Kang Q et al. (2021) | |
| c.2810C>A | p.Ser937Tyr | missense_variant | De novo | - | Simplex | 31278393 | Dyment DA et al. (2019) | |
| c.2968G>A | p.Val990Met | missense_variant | De novo | - | Simplex | 31278393 | Dyment DA et al. (2019) | |
| c.1841A>T | p.Asp614Val | missense_variant | De novo | - | Simplex | 36648066 | Burglen L et al. (2023) | |
| c.3004G>T | p.Val1002Leu | missense_variant | De novo | - | Simplex | 36648066 | Burglen L et al. (2023) | |
| c.3005T>G | p.Val1002Gly | missense_variant | De novo | - | Simplex | 36648066 | Burglen L et al. (2023) | |
| c.3397T>C | p.Ser1133Pro | missense_variant | De novo | - | Simplex | 36648066 | Burglen L et al. (2023) | |
| c.2968G>A | p.Val990Met | missense_variant | De novo | - | Simplex | 34438093 | Gauthier LW et al. (2021) | |
| c.2968G>A | p.Val990Met | missense_variant | De novo | - | - | 32439617 | de Sainte Agathe JM et al. (2020) | |
| c.71G>A | p.Trp24Ter | stop_gained | Familial | Paternal | Multiplex | 37506195 | Cirnigliaro M et al. (2023) | |
| c.3019G>A | p.Gly1007Ser | missense_variant | Familial | Paternal | Simplex | 36648066 | Burglen L et al. (2023) | |
| c.4341_4342del | p.Pro1448PhefsTer7 | frameshift_variant | De novo | - | Simplex | 25363768 | Iossifov I et al. (2014) | |
| c.2002del | p.His668ThrfsTer16 | frameshift_variant | Familial | Paternal | Multiplex | 37506195 | Cirnigliaro M et al. (2023) | |
| c.5075_5084del | p.Lys1692ThrfsTer8 | frameshift_variant | Familial | Maternal | Multiplex | 31398340 | Ruzzo EK , et al. (2019) |
Common Variants
No common variants reported.
SFARI Gene score
S
Syndromic
Score Delta: Score remained at S
criteria met
See SFARI Gene'scoring criteriaThe syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."
Krishnan Probability Score
Score 0.60416745193099
Ranking 354/25841 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.
ExAC Score
Score 7.7375435941234E-6
Ranking 14338/18225 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
Sanders TADA Score
Score 0.65345295387813
Ranking 911/18665 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).
Zhang D Score
Score -0.002646703342634
Ranking 8775/20870 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.