chr3-25729184-G-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_ModerateBP6BP7

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). Synonymous variant affecting the same amino acid position (i.e. G520G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00036 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00067 ( 0 hom. )

Consequence

NGLY1
NM_018297.4 synonymous

Scores

2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 1.41

Publications

1 publications found
Variant links:
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]
NGLY1 Gene-Disease associations (from GenCC):
  • congenital disorder of deglycosylation 1
    Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), G2P
  • NGLY1-deficiency
    Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

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 submission is: [Conflicting_classifications_of_pathogenicity].
BP7
Synonymous conserved (PhyloP=1.41 with no splicing effect.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NGLY1NM_018297.4 linkc.1560C>T p.Gly520Gly synonymous_variant Exon 10 of 12 ENST00000280700.10 NP_060767.2 Q96IV0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NGLY1ENST00000280700.10 linkc.1560C>T p.Gly520Gly synonymous_variant Exon 10 of 12 1 NM_018297.4 ENSP00000280700.5 Q96IV0-1

Frequencies

GnomAD3 genomes
AF:
0.000355
AC:
54
AN:
151996
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000314
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000603
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.000298
AC:
68
AN:
228448
AF XY:
0.000258
show subpopulations
Gnomad AFR exome
AF:
0.000435
Gnomad AMR exome
AF:
0.000205
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000633
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000510
Gnomad OTH exome
AF:
0.000185
GnomAD4 exome
AF:
0.000674
AC:
941
AN:
1396834
Hom.:
0
Cov.:
30
AF XY:
0.000657
AC XY:
456
AN XY:
693792
show subpopulations
African (AFR)
AF:
0.000193
AC:
6
AN:
31066
American (AMR)
AF:
0.000200
AC:
8
AN:
40068
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24308
East Asian (EAS)
AF:
0.0000270
AC:
1
AN:
37018
South Asian (SAS)
AF:
0.00
AC:
0
AN:
75384
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
50976
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5540
European-Non Finnish (NFE)
AF:
0.000831
AC:
894
AN:
1075438
Other (OTH)
AF:
0.000561
AC:
32
AN:
57036
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.438
Heterozygous variant carriers
0
45
90
136
181
226
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
42
84
126
168
210
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000355
AC:
54
AN:
151996
Hom.:
0
Cov.:
32
AF XY:
0.000337
AC XY:
25
AN XY:
74224
show subpopulations
African (AFR)
AF:
0.000314
AC:
13
AN:
41384
American (AMR)
AF:
0.00
AC:
0
AN:
15246
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10588
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.000603
AC:
41
AN:
67984
Other (OTH)
AF:
0.00
AC:
0
AN:
2088
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.496
Heterozygous variant carriers
0
3
6
9
12
15
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.000427
Hom.:
0
Bravo
AF:
0.000374

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
Apr 19, 2021
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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
Feb 02, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

NGLY1-related disorder Benign:1
Apr 15, 2019
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.35
CADD
Benign
10
DANN
Benign
0.64
PhyloP100
1.4

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs138477428; hg19: chr3-25770675; API