15-45362129-A-G
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_001482.3(GATM):c.1252T>C(p.Leu418=) variant causes a synonymous change. The variant allele was found at a frequency of 0.443 in 1,609,502 control chromosomes in the GnomAD database, including 176,650 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Synonymous variant affecting the same amino acid position (i.e. L418L) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.56 ( 27386 hom., cov: 31)
Exomes 𝑓: 0.43 ( 149264 hom. )
Consequence
GATM
NM_001482.3 synonymous
NM_001482.3 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 4.29
Genes affected
GATM (HGNC:4175): (glycine amidinotransferase) This gene encodes a mitochondrial enzyme that belongs to the amidinotransferase family. This enzyme is involved in creatine biosynthesis, whereby it catalyzes the transfer of a guanido group from L-arginine to glycine, resulting in guanidinoacetic acid, the immediate precursor of creatine. Mutations in this gene cause arginine:glycine amidinotransferase deficiency, an inborn error of creatine synthesis characterized by cognitive disability, language impairment, and behavioral disorders. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.53).
BP6
?
Variant 15-45362129-A-G is Benign according to our data. Variant chr15-45362129-A-G is described in ClinVar as [Benign]. Clinvar id is 129137.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-45362129-A-G is described in Lovd as [Benign].
BA1
?
GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.887 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GATM | NM_001482.3 | c.1252T>C | p.Leu418= | synonymous_variant | 9/9 | ENST00000396659.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GATM | ENST00000396659.8 | c.1252T>C | p.Leu418= | synonymous_variant | 9/9 | 1 | NM_001482.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.560 AC: 85103AN: 151898Hom.: 27327 Cov.: 31
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GnomAD3 exomes AF: 0.536 AC: 134200AN: 250570Hom.: 40460 AF XY: 0.520 AC XY: 70501AN XY: 135520
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GnomAD4 exome AF: 0.431 AC: 627625AN: 1457486Hom.: 149264 Cov.: 32 AF XY: 0.433 AC XY: 313857AN XY: 725416
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GnomAD4 genome ? AF: 0.561 AC: 85226AN: 152016Hom.: 27386 Cov.: 31 AF XY: 0.567 AC XY: 42152AN XY: 74294
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ClinVar
Significance: Benign
Submissions summary: Benign:14
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Arginine:glycine amidinotransferase deficiency Benign:5
Benign, reviewed by expert panel | curation | ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen | Jun 06, 2022 | The NM_001482.3:c.1252T>C (p.Leu418=) variant in GATM is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP (BP7). The highest population minor allele frequency in gnomAD v2.1.1 is 0.9186 (18317/19940 alleles) in the East Asian population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.0005), and therefore meets this criterion (BA1). The computational splicing predictor SpliceAI gives a score of 0.0 for donor and acceptor loss suggesting that the variant has no impact on splicing, and the nucleotide is not highly conserved (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 129137). In summary, this variant meets the criteria to be classified as benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BA1, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not specified Benign:4
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Genetic Services Laboratory, University of Chicago | - | Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
not provided Benign:3
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Apr 20, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 29, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 03, 2015 | - - |
Inborn genetic diseases Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 08, 2016 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Fanconi renotubular syndrome 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Aug 10, 2021 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at