rs200561967
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_018297.4(NGLY1):c.622C>T(p.Gln208Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000548 in 1,460,798 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
NGLY1
NM_018297.4 stop_gained
NM_018297.4 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 3.94
Genes affected
NGLY1 (HGNC:17646): (N-glycanase 1) This gene encodes an enzyme that catalyzes hydrolysis of an N(4)-(acetyl-beta-D-glucosaminyl) asparagine residue to N-acetyl-beta-D-glucosaminylamine and a peptide containing an aspartate residue. The encoded enzyme may play a role in the proteasome-mediated degradation of misfolded glycoproteins. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-25751134-G-A is Pathogenic according to our data. Variant chr3-25751134-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 221578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NGLY1 | NM_018297.4 | c.622C>T | p.Gln208Ter | stop_gained | 4/12 | ENST00000280700.10 | NP_060767.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NGLY1 | ENST00000280700.10 | c.622C>T | p.Gln208Ter | stop_gained | 4/12 | 1 | NM_018297.4 | ENSP00000280700 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 250110Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135172
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GnomAD4 exome AF: 0.00000548 AC: 8AN: 1460798Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726698
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GnomAD4 genome Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital disorder of deglycosylation Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2024 | This sequence change creates a premature translational stop signal (p.Gln208*) in the NGLY1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NGLY1 are known to be pathogenic (PMID: 24651605). This variant is present in population databases (rs200561967, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with clinical features of congenital disorder of glycosylation type 1V (PMID: 25900930). ClinVar contains an entry for this variant (Variation ID: 221578). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Medical Biochemical Genetics, National Human Genome institute, NIH, National Institutes of Health | Jan 07, 2016 | - - |
not provided, no classification provided | literature only | GeneReviews | - | Mild impairment - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2019 | The Q208X nonsense variant in the NGLY1 gene has been reported previously in two siblings with features of a NGLY1-related disorder who also had a second variant on the opposite allele (He et al., 2015). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. It is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret Q208X as a pathogenic variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at