rs367567416
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_000156.6(GAMT):c.391+15G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,609,484 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000029 ( 0 hom. )
Consequence
GAMT
NM_000156.6 intron
NM_000156.6 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.601
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 Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 19-1399509-C-A is Pathogenic according to our data. Variant chr19-1399509-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 544259.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}. Variant chr19-1399509-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GAMT | NM_000156.6 | c.391+15G>T | intron_variant | ENST00000252288.8 | |||
GAMT | NM_138924.3 | c.391+15G>T | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GAMT | ENST00000252288.8 | c.391+15G>T | intron_variant | 1 | NM_000156.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
2
AN:
152180
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: 0.0000122 AC: 3AN: 244900Hom.: 0 AF XY: 0.00000753 AC XY: 1AN XY: 132848
GnomAD3 exomes
AF:
AC:
3
AN:
244900
Hom.:
AF XY:
AC XY:
1
AN XY:
132848
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: 0.0000288 AC: 42AN: 1457304Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18AN XY: 724748
GnomAD4 exome
AF:
AC:
42
AN:
1457304
Hom.:
Cov.:
32
AF XY:
AC XY:
18
AN XY:
724748
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: 0.0000131 AC: 2AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74332
GnomAD4 genome
?
AF:
AC:
2
AN:
152180
Hom.:
Cov.:
32
AF XY:
AC XY:
2
AN XY:
74332
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.:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cerebral creatine deficiency syndrome Pathogenic:1Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 18, 2023 | This sequence change falls in intron 3 of the GAMT gene. It does not directly change the encoded amino acid sequence of the GAMT protein. This variant is present in population databases (rs367567416, gnomAD 0.004%). This variant has been observed in individual(s) with primary creatine disorder and GAMT deficiency (PMID: 23234264). ClinVar contains an entry for this variant (Variation ID: 544259). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Nov 02, 2021 | The c.391+15G>T variant in GAMT has been reported in 1 homozygous individual with cerebral creatine deficiency syndrome (PMID: 23234264) and has been identified in in 0.003% (4/125836) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs367567416). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 544259) and has been interpreted as VUS by Invitae. This variant is located in the 3' splice region. In vitro functional studies provide some evidence that the c.391+15G>T variant may slightly impact protein function (PMID: 23234264). However, these types of assays may not accurately represent biological function. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the c.391+15G>T variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PS3_supporting, PM3_supporting, PP3 (Richards 2015). - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 28, 2022 | Variant summary: GAMT c.391+15G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant creates a novel 5' donor site within intron 3. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 244900 control chromosomes (gnomAD). c.391+15G>T has been reported in the literature as a homozygous genotype in an individual affected with Cerebral Creatine Deficiency Syndrome (e.g. Cheillan_2012). Enzyme studies in cells from this individual confirmed deficient GAMT activity, however to our knowledge, no additional experimental evidence demonstrating an impact on protein function has been reported. Two submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at