rs778513258
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_018297.4(NGLY1):c.1235A>T(p.Asp412Val) variant causes a missense change. The variant allele was found at a frequency of 0.000224 in 1,613,580 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D412G) has been classified as Uncertain significance.
Frequency
Consequence
NM_018297.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NGLY1 | NM_018297.4 | c.1235A>T | p.Asp412Val | missense_variant | 8/12 | ENST00000280700.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NGLY1 | ENST00000280700.10 | c.1235A>T | p.Asp412Val | missense_variant | 8/12 | 1 | NM_018297.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000460 AC: 7AN: 152196Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251012Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135666
GnomAD4 exome AF: 0.000242 AC: 354AN: 1461384Hom.: 0 Cov.: 31 AF XY: 0.000248 AC XY: 180AN XY: 726994
GnomAD4 genome ? AF: 0.0000460 AC: 7AN: 152196Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2AN XY: 74362
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 19, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 27, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge - |
Congenital disorder of deglycosylation Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 27, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 412 of the NGLY1 protein (p.Asp412Val). This variant is present in population databases (rs778513258, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with NGLY1-related conditions. ClinVar contains an entry for this variant (Variation ID: 572271). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NGLY1 protein function with a negative predictive value of 80%. 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