chr19-1397348-G-A
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000156.6(GAMT):c.*11C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00312 in 1,607,752 control chromosomes in the GnomAD database, including 139 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).
Frequency
Genomes: 𝑓 0.017 ( 82 hom., cov: 33)
Exomes 𝑓: 0.0016 ( 57 hom. )
Consequence
GAMT
NM_000156.6 3_prime_UTR
NM_000156.6 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.00700
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 Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.91).
BP6
?
Variant 19-1397348-G-A is Benign according to our data. Variant chr19-1397348-G-A is described in ClinVar as [Benign]. Clinvar id is 204598.Status of the report is reviewed_by_expert_panel, 3 stars.
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0571 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAMT | NM_000156.6 | c.*11C>T | 3_prime_UTR_variant | 6/6 | ENST00000252288.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAMT | ENST00000252288.8 | c.*11C>T | 3_prime_UTR_variant | 6/6 | 1 | NM_000156.6 | P1 | ||
GAMT | ENST00000640762.1 | c.*11C>T | 3_prime_UTR_variant | 6/6 | 5 | ||||
GAMT | ENST00000640164.1 | downstream_gene_variant | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0174 AC: 2651AN: 152226Hom.: 82 Cov.: 33
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GnomAD3 exomes AF: 0.00440 AC: 1046AN: 237884Hom.: 25 AF XY: 0.00320 AC XY: 415AN XY: 129596
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GnomAD4 exome AF: 0.00163 AC: 2372AN: 1455408Hom.: 57 Cov.: 30 AF XY: 0.00140 AC XY: 1011AN XY: 723898
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GnomAD4 genome ? AF: 0.0174 AC: 2649AN: 152344Hom.: 82 Cov.: 33 AF XY: 0.0167 AC XY: 1247AN XY: 74490
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ClinVar
Significance: Benign
Submissions summary: Benign:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Deficiency of guanidinoacetate methyltransferase Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Benign, reviewed by expert panel | curation | ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen | Jun 06, 2022 | The NM_000156.6:c.*11C>T variant is a nucleotide substitution in the 3'UTR of GAMT. Because the variant is located in the 3'UTR, it is not expected to alter the amino acid sequence of the gene product. The highest population minor allele frequency in gnomAD v2.1.1 is 0.05828 (1381/23694 alleles) in the African / African-American population, which is higher than the ClinGen CCDS VCEP’s threshold for BA1 (>0.003), and therefore meets this criterion (BA1). Furthermore, the variant has been observed in the homozygous state in 37 individuals out of 134,627 in gnomAD v2.1.1. Given the severity and early onset of the symptoms of GAMT deficiency, this data suggests that the variant does not cause this condition (BS2). It is not predicted to not impact splicing by Splice AI and VarSeak, and the nucleotide is not highly conserved (BP4, BP7). This variant is noted in ClinVar (ID 204598). In summary, this variant meets the criteria to be classified as benign for GAMT deficiency. GAMT-specific ACMG/AMP codes met, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes VCEP (Specifications Version 1.1.0): BA1, BS2, BP4, BP7. (Classification approved by the ClinGen CCDS VCEP on June 6, 2022). - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 10, 2012 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Computational scores
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Name
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BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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