rs202225656
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BS1BP4BS3_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_001482.3:c.692C>G variant in GATM is a missense variant predicted to cause the substitution of a serine by a cysteine at amino acid position 231 (p.Ser231Cys). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00022 (28/129044 alleles) in the European (non-Finnish) population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0001), and therefore meets this criterion (BS1). Expression of the variant in HeLa cells resulted in 100% wild type AGAT activity indicating that this variant does not impact protein function (PMID:27233232) (BS3_Supporting). The computational predictor REVEL gives a score of 0.078 which is below the threshold of 0.15, evidence that does not predict a damaging effect on AGAT function (BP4). There is a ClinVar entry for this variant (Variation ID: 205616). In summary, this variant meets the criteria to be classified as likely benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BS1, BS3_Supporting, BP4.(Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 20, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA314874/MONDO:0012996/025
Frequency
Consequence
NM_001482.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GATM | NM_001482.3 | c.692C>G | p.Ser231Cys | missense_variant | 5/9 | ENST00000396659.8 | NP_001473.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GATM | ENST00000396659.8 | c.692C>G | p.Ser231Cys | missense_variant | 5/9 | 1 | NM_001482.3 | ENSP00000379895.3 |
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152176Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000995 AC: 25AN: 251294Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135830
GnomAD4 exome AF: 0.000220 AC: 322AN: 1461790Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 147AN XY: 727204
GnomAD4 genome AF: 0.000164 AC: 25AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74350
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1Other:1
not provided, no classification provided | in vitro | Hospital for Sick Children | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 17, 2021 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function This variant is associated with the following publications: (PMID: 27233232) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 20, 2017 | - - |
Arginine:glycine amidinotransferase deficiency Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 01, 2022 | This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 231 of the GATM protein (p.Ser231Cys). This variant is present in population databases (rs202225656, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 205616). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change does not substantially affect GATM function (PMID: 27233232). 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. - |
Likely benign, reviewed by expert panel | curation | ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel, ClinGen | Aug 20, 2024 | The NM_001482.3:c.692C>G variant in GATM is a missense variant predicted to cause the substitution of a serine by a cysteine at amino acid position 231 (p.Ser231Cys). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00022 (28/129044 alleles) in the European (non-Finnish) population, which is higher than the ClinGen CCDS VCEP’s threshold for BS1 (>0.0001), and therefore meets this criterion (BS1). Expression of the variant in HeLa cells resulted in 100% wild type AGAT activity indicating that this variant does not impact protein function (PMID: 27233232) (BS3_Supporting). The computational predictor REVEL gives a score of 0.078 which is below the threshold of 0.15, evidence that does not predict a damaging effect on AGAT function (BP4). There is a ClinVar entry for this variant (Variation ID: 205616). In summary, this variant meets the criteria to be classified as likely benign for AGAT deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel (Specifications Version 1.1.0): BS1, BS3_Supporting, BP4. (Classification approved by the ClinGen Cerebral Creatine Deficiency Syndromes Variant Curation Expert Panel on August 20, 2024). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at