rs745814294
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP5BP4BP7
The NM_018297.4(NGLY1):c.930C>T(p.Gly310=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,656 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: not found (cov: 32)
Exomes 𝑓: 0.0000055 ( 0 hom. )
Consequence
NGLY1
NM_018297.4 synonymous
NM_018297.4 synonymous
Scores
1
1
Clinical Significance
Conservation
PhyloP100: 0.510
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 3-25737407-G-A is Pathogenic according to our data. Variant chr3-25737407-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221583.We mark this variant Likely_pathogenic, oryginal submissions are: {not_provided=1, Likely_pathogenic=1, Uncertain_significance=1}.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.29).. Strength limited to SUPPORTING due to the PP5.
BP7
?
Synonymous conserved (PhyloP=0.51 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NGLY1 | NM_018297.4 | c.930C>T | p.Gly310= | synonymous_variant | 6/12 | ENST00000280700.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NGLY1 | ENST00000280700.10 | c.930C>T | p.Gly310= | synonymous_variant | 6/12 | 1 | NM_018297.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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32
GnomAD3 exomes AF: 0.00000797 AC: 2AN: 251018Hom.: 0 AF XY: 0.00000737 AC XY: 1AN XY: 135656
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GnomAD4 exome AF: 0.00000547 AC: 8AN: 1461656Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 727142
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Congenital disorder of deglycosylation Pathogenic:1Uncertain:1Other:1
not provided, no classification provided | literature only | GeneReviews | - | Splice site variant. Mild impairment - |
Pathogenic, no assertion criteria provided | clinical testing | Medical Biochemical Genetics, National Human Genome institute, NIH, National Institutes of Health | Jan 07, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 19, 2022 | This sequence change affects codon 310 of the NGLY1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NGLY1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 25 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs745814294, gnomAD 0.002%). This variant has been observed in individual(s) with NGLY1-related conditions (PMID: 25900930). ClinVar contains an entry for this variant (Variation ID: 221583). Studies have shown that this variant results in the activation of a cryptic splice site in exon 6 (PMID: 32123317). 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
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Name
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BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
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
DS_DG_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at