rs150338273
Positions:
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
Genomes: 𝑓 0.00037 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00052 ( 2 hom. )
Consequence
GAMT
NM_000156.6 missense
NM_000156.6 missense
Scores
11
8
Clinical Significance
Conservation
PhyloP100: 6.65
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PM1
In a helix (size 5) in uniprot entity GAMT_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000156.6
BP4
Computational evidence support a benign effect (MetaRNN=0.2776612).
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000525 (764/1456374) while in subpopulation NFE AF= 0.000668 (742/1110366). AF 95% confidence interval is 0.000628. There are 2 homozygotes in gnomad4_exome. There are 401 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GAMT | NM_000156.6 | c.227C>T | p.Ser76Leu | missense_variant | 2/6 | ENST00000252288.8 | NP_000147.1 | |
GAMT | NM_138924.3 | c.227C>T | p.Ser76Leu | missense_variant | 2/5 | NP_620279.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GAMT | ENST00000252288.8 | c.227C>T | p.Ser76Leu | missense_variant | 2/6 | 1 | NM_000156.6 | ENSP00000252288 | P1 | |
GAMT | ENST00000447102.8 | c.227C>T | p.Ser76Leu | missense_variant | 2/5 | 2 | ENSP00000403536 | |||
GAMT | ENST00000640762.1 | c.158C>T | p.Ser53Leu | missense_variant | 2/6 | 5 | ENSP00000492031 |
Frequencies
GnomAD3 genomes AF: 0.000375 AC: 57AN: 152188Hom.: 1 Cov.: 32
GnomAD3 genomes
AF:
AC:
57
AN:
152188
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000254 AC: 61AN: 239916Hom.: 0 AF XY: 0.000230 AC XY: 30AN XY: 130322
GnomAD3 exomes
AF:
AC:
61
AN:
239916
Hom.:
AF XY:
AC XY:
30
AN XY:
130322
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000525 AC: 764AN: 1456374Hom.: 2 Cov.: 33 AF XY: 0.000554 AC XY: 401AN XY: 723976
GnomAD4 exome
AF:
AC:
764
AN:
1456374
Hom.:
Cov.:
33
AF XY:
AC XY:
401
AN XY:
723976
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.000374 AC: 57AN: 152306Hom.: 1 Cov.: 32 AF XY: 0.000282 AC XY: 21AN XY: 74476
GnomAD4 genome
AF:
AC:
57
AN:
152306
Hom.:
Cov.:
32
AF XY:
AC XY:
21
AN XY:
74476
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
4
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
8
ExAC
AF:
AC:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jan 09, 2017 | - - |
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Apr 05, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 05, 2024 | Reported as a heterozygous variant in a newborn; however, additional clinical information was not provided (PMID: 26319512); 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, 26319512) - |
Deficiency of guanidinoacetate methyltransferase Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago | Mar 30, 2021 | 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 17, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 18, 2023 | 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
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Oct 25, 2022 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Uncertain
D;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;M
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;.;D
REVEL
Uncertain
Sift
Uncertain
D;.;D
Sift4G
Uncertain
D;.;D
Polyphen
P;.;.
Vest4
MVP
MPC
0.14
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at