3-25783328-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_018297.4(NGLY1):​c.63C>A​(p.Cys21*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000416 in 1,442,126 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000042 ( 0 hom. )

Consequence

NGLY1
NM_018297.4 stop_gained

Scores

3
3
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 0.357
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]
OXSM (HGNC:26063): (3-oxoacyl-ACP synthase, mitochondrial) This gene encodes a beta-ketoacyl synthetase. The encoded enzyme is required for elongation of fatty acid chains in the mitochondria. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2009]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-25783328-G-T is Pathogenic according to our data. Variant chr3-25783328-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2895077.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NGLY1NM_018297.4 linkuse as main transcriptc.63C>A p.Cys21* stop_gained 1/12 ENST00000280700.10 NP_060767.2 Q96IV0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NGLY1ENST00000280700.10 linkuse as main transcriptc.63C>A p.Cys21* stop_gained 1/121 NM_018297.4 ENSP00000280700.5 Q96IV0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000416
AC:
6
AN:
1442126
Hom.:
0
Cov.:
34
AF XY:
0.00000279
AC XY:
2
AN XY:
715916
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000544
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJul 13, 2023This sequence change creates a premature translational stop signal (p.Cys21*) in the NGLY1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NGLY1 are known to be pathogenic (PMID: 24651605). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NGLY1-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.55
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.78
D
Vest4
0.15
GERP RS
2.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1182383020; hg19: chr3-25824819; API