rs745872044
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5
The ENST00000354202.9(DPAGT1):c.790G>A(p.Val264Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000867 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V264G) has been classified as Pathogenic.
Frequency
Consequence
ENST00000354202.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DPAGT1 | NM_001382.4 | c.790G>A | p.Val264Met | missense_variant | 6/9 | ENST00000354202.9 | NP_001373.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DPAGT1 | ENST00000354202.9 | c.790G>A | p.Val264Met | missense_variant | 6/9 | 1 | NM_001382.4 | ENSP00000346142 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152180Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251490Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135922
GnomAD4 exome AF: 0.00000752 AC: 11AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727246
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74342
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jan 13, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 20, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); 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: 24759841, 30388443) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 21, 2021 | - - |
DPAGT1-congenital disorder of glycosylation;C3553645:Congenital myasthenic syndrome 13 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 13, 2022 | 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. This variant disrupts the p.Val264 amino acid residue in DPAGT1. Other variant(s) that disrupt this residue have been observed in individuals with DPAGT1-related conditions (PMID: 22742743, 28662078), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects DPAGT1 function (PMID: 24759841). 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: "Probably Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 582259). This missense change has been observed in individual(s) with congenital myasthenic syndrome (PMID: 24759841). This variant is present in population databases (rs745872044, gnomAD 0.008%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 264 of the DPAGT1 protein (p.Val264Met). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at