Human Gene Module / Chromosome 3 / AMT

AMTAminomethyltransferase

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
3 / 3
Rare Variants / Common Variants
4 / 0
Aliases
AMT, GCE,  GCST,  GCVT,  NKH
Associated Syndromes
-
Chromosome Band
3p21.31
Associated Disorders
-
Relevance to Autism

Homozygous missense variants in the AMT gene were identified that segregated with ASD in two separate pedigrees (one multiplex, one simplex) consisting of affected children born to consanguineous parents (Yu et al., 2013).

Molecular Function

This gene encodes one of four critical components of the glycine cleavage system. Mutations in this gene have been associated with glycine encephalopathy.

External Links
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SFARI Genomic Platforms
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Reports related to AMT (3 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Using whole-exome sequencing to identify inherited causes of autism Yu TW , et al. (2013) Yes -
2 Support - Cirnigliaro M et al. (2023) Yes -
3 Support - Yasser Al-Sarraj et al. (2024) Yes -
Rare Variants   (4)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.593A>G p.Asp198Gly missense_variant Familial Both parents Simplex 23352163 Yu TW , et al. (2013)
c.922A>T p.Ile308Phe missense_variant Familial Both parents Multiplex 23352163 Yu TW , et al. (2013)
c.635T>C p.Val212Ala missense_variant Familial Both parents Unknown 38572415 Yasser Al-Sarraj et al. (2024)
c.1209del p.Lys403AsnfsTer34 frameshift_variant Familial Paternal Multiplex (monozygotic twins) 37506195 Cirnigliaro M et al. (2023)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Homozygous missense variants in AMT were found to segregate with ASD in two consanguineous families (one multiplex, one simplex) in Yu et al., 2013; biochemical analysis of the missense variant found in the multiplex family (p.Ile308Phe) demonstrated protein misfolding and aggregation, as well as partial loss-of-function of glycine cleavage and synthesis activity. Defects in AMT are a cause of non-ketotic hyperglycinemia (NKH) [MIM:605899], also known as glycine encephalopathy (GCE), an autosomal recessive disease characterized by accumulation of a large amount of glycine in body fluid and by severe neurological symptoms.

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

Homozygous missense variants in AMT were found to segregate with ASD in two consanguineous families (one multiplex, one simplex) in Yu et al., 2013; biochemical analysis of the missense variant found in the multiplex family (p.Ile308Phe) demonstrated protein misfolding and aggregation, as well as partial loss-of-function of glycine cleavage and synthesis activity. Defects in AMT are a cause of non-ketotic hyperglycinemia (NKH) [MIM:605899], also known as glycine encephalopathy (GCE), an autosomal recessive disease characterized by accumulation of a large amount of glycine in body fluid and by severe neurological symptoms.

Reports Added
[New Scoring Scheme]
4/1/2016
icon
3

Increased from to 3

Description

Homozygous missense variants in AMT were found to segregate with ASD in two consanguineous families (one multiplex, one simplex) in Yu et al., 2013; biochemical analysis of the missense variant found in the multiplex family (p.Ile308Phe) demonstrated protein misfolding and aggregation, as well as partial loss-of-function of glycine cleavage and synthesis activity. Defects in AMT are a cause of non-ketotic hyperglycinemia (NKH) [MIM:605899], also known as glycine encephalopathy (GCE), an autosomal recessive disease characterized by accumulation of a large amount of glycine in body fluid and by severe neurological symptoms.

Krishnan Probability Score

Score 0.32833826770398

Ranking 25138/25841 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 0.0005694752865856

Ranking 12135/18225 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 0.93336899357834

Ranking 12249/18665 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
Larsen Cumulative Evidence Score

Score 19

Ranking 107/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
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