3-49420248-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate
The NM_000481.4(AMT):c.434A>G(p.Asn145Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,614,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N145I) has been classified as Pathogenic.
Frequency
Consequence
NM_000481.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
AMT | NM_000481.4 | c.434A>G | p.Asn145Ser | missense_variant | Exon 4 of 9 | ENST00000273588.9 | NP_000472.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
AMT | ENST00000273588.9 | c.434A>G | p.Asn145Ser | missense_variant | Exon 4 of 9 | 1 | NM_000481.4 | ENSP00000273588.3 | ||
ENSG00000283189 | ENST00000636166.1 | c.671A>G | p.Asn224Ser | missense_variant | Exon 6 of 11 | 5 | ENSP00000490106.1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152208Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251492Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135922
GnomAD4 exome AF: 0.0000280 AC: 41AN: 1461888Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17AN XY: 727246
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74362
ClinVar
Submissions by phenotype
Glycine encephalopathy Uncertain:1
This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 145 of the AMT protein (p.Asn145Ser). This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with AMT-related conditions. ClinVar contains an entry for this variant (Variation ID: 856726). 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: "Possibly Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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