rs150338273
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4BS1_SupportingBS2
The NM_000156.6(GAMT):c.227C>T(p.Ser76Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00051 in 1,608,680 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_000156.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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GAMT | ENST00000252288.8 | c.227C>T | p.Ser76Leu | missense_variant | Exon 2 of 6 | 1 | NM_000156.6 | ENSP00000252288.1 | ||
GAMT | ENST00000447102.8 | c.227C>T | p.Ser76Leu | missense_variant | Exon 2 of 5 | 2 | ENSP00000403536.2 | |||
GAMT | ENST00000640762.1 | c.158C>T | p.Ser53Leu | missense_variant | Exon 2 of 6 | 5 | ENSP00000492031.1 |
Frequencies
GnomAD3 genomes AF: 0.000375 AC: 57AN: 152188Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.000254 AC: 61AN: 239916Hom.: 0 AF XY: 0.000230 AC XY: 30AN XY: 130322
GnomAD4 exome AF: 0.000525 AC: 764AN: 1456374Hom.: 2 Cov.: 33 AF XY: 0.000554 AC XY: 401AN XY: 723976
GnomAD4 genome AF: 0.000374 AC: 57AN: 152306Hom.: 1 Cov.: 32 AF XY: 0.000282 AC XY: 21AN XY: 74476
ClinVar
Submissions by phenotype
not provided Uncertain:4
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Published functional studies demonstrate that S76L does not damage the protein function (PMID: 26319512); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26003046, 28758966, 26319512) -
Deficiency of guanidinoacetate methyltransferase Uncertain:4
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GAMT NM_000156.5 exon 2 p.Ser76Leu (c.227C>T): This variant has been reported in the literature in 1 individual, but without phenotype information (Mercimek-Mahmutoglu 2016 PMID:26319512). This variant is present in 0.05% (66/123594) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/19-1399892-G-A). This variant is present in ClinVar (Variation ID:195022). Evolutionary conservation suggests that this variant may not impact the protein; computational predictive tools for this variant are unclear. Functional studies suggest a benign effect of this variant. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
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Inborn genetic diseases Uncertain:1
The c.227C>T (p.S76L) alteration is located in exon 2 (coding exon 2) of the GAMT gene. This alteration results from a C to T substitution at nucleotide position 227, causing the serine (S) at amino acid position 76 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
Cerebral creatine deficiency syndrome Uncertain:1
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 76 of the GAMT protein (p.Ser76Leu). This variant is present in population databases (rs150338273, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with GAMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 195022). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GAMT protein function. Experimental studies have shown that this missense change does not substantially affect GAMT function (PMID: 26319512). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at