rs376982466
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1PP3
The NM_001482.3(GATM):c.541G>A(p.Glu181Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000185 in 1,461,814 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 Uncertain significance (★★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
GATM
NM_001482.3 missense
NM_001482.3 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 7.48
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 Uncertain_significance. Variant got 3 ACMG points.
PM1
?
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001482.3
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.836
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GATM | NM_001482.3 | c.541G>A | p.Glu181Lys | missense_variant | 4/9 | ENST00000396659.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GATM | ENST00000396659.8 | c.541G>A | p.Glu181Lys | missense_variant | 4/9 | 1 | NM_001482.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251386Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135866
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GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461814Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 727214
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GnomAD4 genome ? Cov.: 32
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Bravo
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ESP6500AA
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Arginine:glycine amidinotransferase deficiency Uncertain:2
Uncertain significance, reviewed by expert panel | curation | ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen | Jan 24, 2023 | The NM_001482.3:c.541G>A variant in GATM is a missense variant that is predicted to result in the substitution of glutamine by lysine at amino acid 181 (p.Glu181Lys). The highest population minor allele frequency for this variant in gnomAD v2.1.1 is 0.00001 (1/113714 alleles) in the European (non-Finnish) population, which is lower than the ClinGen CCDS VCEP’s threshold for PM2_Supporting (<0.000055), meeting this criterion (PM2_Supporting). When overexpressed in HeLa cells, the variant resulted in <15% wild-type enzyme activity (PMID: 27233232). The computational predictor REVEL gives a score of 0.608, which neither predicts a damaging nor a benign inpact on AGAT function. To our knowledge, this variant has not been reported in an individual with AGAT deficiency in the published literature. There is a ClinVar entry for this variant (Variation ID: 225914). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for AGAT deficiency. GATM-specific ACMG/AMP criteria applied, as specified by the ClinGen CCDS VCEP (Specifications Version 1.1.0): PS3_Supporting, PM2_Supporting. (Classification approved by the ClinGen CCDS VCEP on January 24, 2023). - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 181 of the GATM protein (p.Glu181Lys). This variant is present in population databases (rs376982466, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with GATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 225914). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GATM protein function. Experimental studies have shown that this missense change affects GATM function (PMID: 27233232). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
not provided Other:1
not provided, no classification provided | in vitro | Hospital for Sick Children | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Uncertain
D;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Uncertain
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;.
Polyphen
D;D;.
Vest4
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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Calibrated prediction
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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