11-119100396-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The NM_001382.4(DPAGT1):āc.509A>Gā(p.Tyr170Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,044 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).
Frequency
Consequence
NM_001382.4 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 | UniProt |
---|---|---|---|---|---|---|---|
DPAGT1 | NM_001382.4 | c.509A>G | p.Tyr170Cys | missense_variant | 4/9 | ENST00000354202.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DPAGT1 | ENST00000354202.9 | c.509A>G | p.Tyr170Cys | missense_variant | 4/9 | 1 | NM_001382.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000329 AC: 5AN: 152042Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251314Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135840
GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461884Hom.: 0 Cov.: 33 AF XY: 0.0000138 AC XY: 10AN XY: 727246
GnomAD4 genome AF: 0.0000329 AC: 5AN: 152160Hom.: 0 Cov.: 33 AF XY: 0.0000403 AC XY: 3AN XY: 74392
ClinVar
Submissions by phenotype
Congenital disorder of glycosylation Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | University of Washington Center for Mendelian Genomics, University of Washington | - | - - |
DPAGT1-congenital disorder of glycosylation Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2003 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 21, 2021 | Identified in trans with another DPAGT1 missense variant, p.A195G, in two siblings with abnormal neurological findings, with one sibling reported to have abnormal transferrin studies consistent with a type 1 congenital disorder of glycosylation (Kane et al., 2016; Ng et al., 2019); Published functional studies demonstrate a damaging effect: reduced N-acetyl-glucosamine-1 phosphate transferase (GPT) activity in in vitro assays (Wu et al., 2003); Identified in a patient with congenital disorder of glycosylation type 1j who reportedly harbored a second unknown variant in trans which resulted in decreased mRNA levels (Wu et al., 2003); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (Stenson et al., 2014); This variant is associated with the following publications: (PMID: 30117111, 12872255, 26805780, 31519321, 30388443, 22304930, 23249953, 22742743) - |
DPAGT1-congenital disorder of glycosylation;C3553645:Congenital myasthenic syndrome 13 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 15, 2022 | 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 C0"). 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. Experimental studies have shown that this missense change affects DPAGT1 function (PMID: 12872255). ClinVar contains an entry for this variant (Variation ID: 12296). This variant is also known as c.660A>G. This missense change has been observed in individual(s) with congenital disorder of glycosylation 1J (CDG-Ij) (PMID: 12872255, 30117111). This variant is present in population databases (rs28934876, gnomAD 0.004%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 170 of the DPAGT1 protein (p.Tyr170Cys). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at