rs781163821
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePM2
The NM_000156.6(GAMT):c.668_669insA(p.Tyr223Ter) variant causes a stop gained, frameshift change. The variant allele was found at a frequency of 0.00000186 in 1,612,302 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★★). Synonymous variant affecting the same amino acid position (i.e. Y223Y) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
GAMT
NM_000156.6 stop_gained, frameshift
NM_000156.6 stop_gained, frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.00
Genes affected
GAMT (HGNC:4136): (guanidinoacetate N-methyltransferase) The protein encoded by this gene is a methyltransferase that converts guanidoacetate to creatine, using S-adenosylmethionine as the methyl donor. Defects in this gene have been implicated in neurologic syndromes and muscular hypotonia, probably due to creatine deficiency and accumulation of guanidinoacetate in the brain of affected individuals. Two transcript variants encoding different isoforms have been described for this gene. Pseudogenes of this gene are found on chromosomes 2 and 13. [provided by RefSeq, Feb 2012]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0605 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAMT | NM_000156.6 | c.668_669insA | p.Tyr223Ter | stop_gained, frameshift_variant | 6/6 | ENST00000252288.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAMT | ENST00000252288.8 | c.668_669insA | p.Tyr223Ter | stop_gained, frameshift_variant | 6/6 | 1 | NM_000156.6 | P1 | |
GAMT | ENST00000640762.1 | c.599_600insA | p.Tyr200Ter | stop_gained, frameshift_variant | 6/6 | 5 | |||
GAMT | ENST00000640164.1 | n.501_502insA | non_coding_transcript_exon_variant | 4/4 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248204Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134760
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460102Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726362
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Deficiency of guanidinoacetate methyltransferase Uncertain:2
Uncertain significance, reviewed by expert panel | curation | ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen | Jun 06, 2022 | The NM_000156.6:c.668dupA (p.Tyr223fs) variant in GAMT is a frameshift variant in the last exon (exon 6/6; amino acid 223/237) of GAMT, and is therefore predicted to escape nonsense mediated decay. Less than 10% of the protein is predicted to be removed (PVS1_Moderate). The variant is absent in gnomAD v2.1.1 (PM2_Supporting). To our knowledge, this variant has not been reported in published literature in individuals with GAMT deficiency. It is noted in ClinVar (Variation ID 445930). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): PM2_Supporting, BP4. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Aug 16, 2017 | - - |
Cerebral creatine deficiency syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 26, 2022 | Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. ClinVar contains an entry for this variant (Variation ID: 445930). This variant has not been reported in the literature in individuals affected with GAMT-related conditions. This variant is present in population databases (rs781163821, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Tyr223*) in the GAMT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 14 amino acid(s) of the GAMT protein. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at