rs397514708
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001482.3(GATM):c.505C>T(p.Arg169Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000031 in 1,613,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
GATM
NM_001482.3 stop_gained
NM_001482.3 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 4.34
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 Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 15-45368240-G-A is Pathogenic according to our data. Variant chr15-45368240-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 55919.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr15-45368240-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GATM | NM_001482.3 | c.505C>T | p.Arg169Ter | stop_gained | 4/9 | ENST00000396659.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GATM | ENST00000396659.8 | c.505C>T | p.Arg169Ter | stop_gained | 4/9 | 1 | NM_001482.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152124Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251320Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135838
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461670Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727148
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Arginine:glycine amidinotransferase deficiency Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change creates a premature translational stop signal (p.Arg169*) in the GATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GATM are known to be pathogenic (PMID: 11555793). This variant is present in population databases (rs397514708, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with arginine:glycine amidinotransferase (AGAT) deficiency (PMID: 20625172). ClinVar contains an entry for this variant (Variation ID: 55919). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, reviewed by expert panel | curation | ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen | Jun 06, 2022 | The NM_001482.3(GATM):c.505C>T (p.Arg169Ter) variant in GATM is a nonsense variant predicted to cause a premature stop codon in biologically-relevant-exon 4/9 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is reported to be homozygous in a proband and sibling, both of whom have undetectable GAA in plasma and urine, and reduced creatine peak (about 2/3 normal) on brain MRS with elevated NAA/creatine ratio (PMID 20625172, 23660394, 26490222)(PP4_Strong, PM3_Supporting). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00005 in the East Asian population. This is lower than the ClinGen CCDS VCEP's threshold for PM2_Supporting (<0.000055) meeting this criterion (PM2_Supporting). There is a ClinVar entry for this variant (Variation ID: 55919). In summary, this variant meets the criteria to be classified as pathogenic for AGAT deficiency. GATM-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PVS1, PP4_Strong, PM3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2013 | - - |
Arginine:glycine amidinotransferase deficiency;C4551503:Fanconi renotubular syndrome 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 06, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at