rs753743263
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP5BP4
The ENST00000395338.7(AMT):c.-58C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,388,010 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
Consequence
ENST00000395338.7 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NICN1 | ENST00000273598 | c.*2325C>T | 3_prime_UTR_variant | Exon 6 of 6 | 1 | NM_032316.3 | ENSP00000273598.4 | |||
ENSG00000283189 | ENST00000636166.1 | c.496-936C>T | intron_variant | Intron 4 of 10 | 5 | ENSP00000490106.1 | ||||
AMT | ENST00000273588.9 | c.-58C>T | upstream_gene_variant | 1 | NM_000481.4 | ENSP00000273588.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000502 AC: 1AN: 199220Hom.: 0 AF XY: 0.00000921 AC XY: 1AN XY: 108570
GnomAD4 exome AF: 7.20e-7 AC: 1AN: 1388010Hom.: 0 Cov.: 23 AF XY: 0.00000145 AC XY: 1AN XY: 691738
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Glycine encephalopathy Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Dec 06, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 28, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 555489). This variant has been observed in individual(s) with glycine encephalopathy (PMID: 27362913; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs753743263, gnomAD 0.001%). This variant occurs in a non-coding region of the AMT gene. It does not change the encoded amino acid sequence of the AMT protein. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 11, 2023 | Variant summary: AMT c.-58C>T is located in the untranscribed region upstream of the AMT gene region. The variant allele was found at a frequency of 5e-06 in 199220 control chromosomes (gnomAD). c.-58C>T has been reported in the literature in three alleles from individuals affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia), including at least one case where it was found in trans with a pathogenic variant (Coughlin_2017); however, the remaining two alleles were reported as an uninformative genotype (i.e. zygosity not specified). These data do not allow any strong conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Yet it has been noted that several 5'UTR variants located within nucleotides c.-55 to c.-66 were observed in affected individuals from the Coughlin_2017 study cohort, suggesting this could represent a regulatory region for the AMT gene. The following publication has been ascertained in the context of this evaluation (PMID: 27362913). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. One submitter, also citing internal data, classified the variant as pathogenic, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic until further clinical and/or functional data becomes available. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at