rs138477428
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_ModerateBP6BP7BS1
The NM_018297.4(NGLY1):c.1560C>T(p.Gly520Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000642 in 1,548,830 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00067 ( 0 hom. )
Consequence
NGLY1
NM_018297.4 synonymous
NM_018297.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.41
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 Likely_benign. Variant got -6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.35).
BP6
Variant 3-25729184-G-A is Benign according to our data. Variant chr3-25729184-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 474213.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BP7
Synonymous conserved (PhyloP=1.41 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000674 (941/1396834) while in subpopulation NFE AF= 0.000831 (894/1075438). AF 95% confidence interval is 0.000785. There are 0 homozygotes in gnomad4_exome. There are 456 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NGLY1 | NM_018297.4 | c.1560C>T | p.Gly520Gly | synonymous_variant | 10/12 | ENST00000280700.10 | NP_060767.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NGLY1 | ENST00000280700.10 | c.1560C>T | p.Gly520Gly | synonymous_variant | 10/12 | 1 | NM_018297.4 | ENSP00000280700.5 |
Frequencies
GnomAD3 genomes AF: 0.000355 AC: 54AN: 151996Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000298 AC: 68AN: 228448Hom.: 0 AF XY: 0.000258 AC XY: 32AN XY: 124260
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GnomAD4 exome AF: 0.000674 AC: 941AN: 1396834Hom.: 0 Cov.: 30 AF XY: 0.000657 AC XY: 456AN XY: 693792
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GnomAD4 genome AF: 0.000355 AC: 54AN: 151996Hom.: 0 Cov.: 32 AF XY: 0.000337 AC XY: 25AN XY: 74224
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 19, 2021 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. - |
Congenital disorder of deglycosylation Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
NGLY1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Apr 15, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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