rs202027326
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_018297.4(NGLY1):āc.818G>Cā(p.Trp273Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000967 in 1,614,004 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 Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000059 ( 0 hom., cov: 32)
Exomes š: 0.00010 ( 0 hom. )
Consequence
NGLY1
NM_018297.4 missense
NM_018297.4 missense
Scores
6
9
3
Clinical Significance
Conservation
PhyloP100: 7.71
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.781
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NGLY1 | NM_018297.4 | c.818G>C | p.Trp273Ser | missense_variant | 5/12 | ENST00000280700.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NGLY1 | ENST00000280700.10 | c.818G>C | p.Trp273Ser | missense_variant | 5/12 | 1 | NM_018297.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000592 AC: 9AN: 152154Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
9
AN:
152154
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000756 AC: 19AN: 251234Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135754
GnomAD3 exomes
AF:
AC:
19
AN:
251234
Hom.:
AF XY:
AC XY:
8
AN XY:
135754
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000101 AC: 147AN: 1461850Hom.: 0 Cov.: 31 AF XY: 0.0000921 AC XY: 67AN XY: 727224
GnomAD4 exome
AF:
AC:
147
AN:
1461850
Hom.:
Cov.:
31
AF XY:
AC XY:
67
AN XY:
727224
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000592 AC: 9AN: 152154Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74308
GnomAD4 genome
?
AF:
AC:
9
AN:
152154
Hom.:
Cov.:
32
AF XY:
AC XY:
4
AN XY:
74308
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
1
ESP6500EA
AF:
AC:
2
ExAC
?
AF:
AC:
14
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Congenital disorder of deglycosylation Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2022 | This sequence change replaces tryptophan, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 273 of the NGLY1 protein (p.Trp273Ser). This variant is present in population databases (rs202027326, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with NGLY1-related conditions. ClinVar contains an entry for this variant (Variation ID: 541262). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 23, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Benign
T;T;D;T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;M;M;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D;D
Sift4G
Benign
T;T;T;T;T
Polyphen
B;D;P;.;.
Vest4
MVP
MPC
0.29
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at