rs587777265
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_018297.4(NGLY1):c.1370_1371insG(p.Arg458LysfsTer14) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
NGLY1
NM_018297.4 frameshift
NM_018297.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.34
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 3-25732373-T-TC is Pathogenic according to our data. Variant chr3-25732373-T-TC is described in ClinVar as [Pathogenic]. Clinvar id is 126422.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NGLY1 | NM_018297.4 | c.1370_1371insG | p.Arg458LysfsTer14 | frameshift_variant | 9/12 | ENST00000280700.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NGLY1 | ENST00000280700.10 | c.1370_1371insG | p.Arg458LysfsTer14 | frameshift_variant | 9/12 | 1 | NM_018297.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital disorder of deglycosylation Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | May 24, 2013 | This frameshift variant is categorized as deleterious according to ACMG guidelines (PMID:18414213) and was found once in our laboratory homozygous in a 19-year-old female with static encephalopathy, peripheral neuropathy, dysphagia, intellectual disability, abnormal movements, abnormal tone, cortical visual impairment, osteoporosis, scoliosis. This patient has since been published (PMID: 24651605). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 20, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 03, 2023 | This sequence change creates a premature translational stop signal (p.Arg458Lysfs*14) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with N-glycanase 1 deficiency (PMID: 24651605, 27388694). ClinVar contains an entry for this variant (Variation ID: 126422). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 20, 2019 | The c.1370dupG pathogenic variant in the NGLY1 gene has been reported previously as a homozygous pathogenic variant in a patient with features of NGLY1 deficiency (Enns et al., 2014; Lam et al., 2017). The duplication causes a frameshift starting with codon Arginine 458, changes this amino acid to a Lysine residue and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Arg458LysfsX14. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.1370dupG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1370dupG as a pathogenic variant. - |
Computational scores
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Calibrated prediction
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Prediction
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