rs1375323331
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_018297.4(NGLY1):c.857_873del(p.Cys286PhefsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 152,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Consequence
NGLY1
NM_018297.4 frameshift
NM_018297.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.82
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 12 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 3-25739584-ATCGATTGCTGAACTGGC-A is Pathogenic according to our data. Variant chr3-25739584-ATCGATTGCTGAACTGGC-A is described in ClinVar as [Pathogenic]. Clinvar id is 541255.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NGLY1 | NM_018297.4 | c.857_873del | p.Cys286PhefsTer5 | frameshift_variant | 5/12 | ENST00000280700.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NGLY1 | ENST00000280700.10 | c.857_873del | p.Cys286PhefsTer5 | frameshift_variant | 5/12 | 1 | NM_018297.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 32
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GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152214Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74368
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital disorder of deglycosylation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2020 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in NGLY1 are known to be pathogenic (PMID: 24651605). This variant has not been reported in the literature in individuals with NGLY1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys286Phefs*5) in the NGLY1 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at