3-25732390-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000280700.10(NGLY1):​c.1354C>A​(p.Pro452Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,498 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P452R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

NGLY1
ENST00000280700.10 missense

Scores

2
17

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.93
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13342339).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NGLY1NM_018297.4 linkuse as main transcriptc.1354C>A p.Pro452Thr missense_variant 9/12 ENST00000280700.10 NP_060767.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NGLY1ENST00000280700.10 linkuse as main transcriptc.1354C>A p.Pro452Thr missense_variant 9/121 NM_018297.4 ENSP00000280700 P1Q96IV0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251300
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135820
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461498
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727054
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:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.073
BayesDel_addAF
Benign
-0.15
T
BayesDel_noAF
Benign
-0.44
CADD
Benign
23
DANN
Benign
0.96
DEOGEN2
Benign
0.21
.;T;.;T;.
Eigen
Benign
-0.15
Eigen_PC
Benign
0.018
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.87
D;D;D;D;D
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.13
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.7
.;L;L;.;.
MutationTaster
Benign
0.99
D;D;D;D;D
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-2.0
N;N;N;N;N
REVEL
Benign
0.086
Sift
Benign
0.072
T;T;T;T;T
Sift4G
Benign
0.18
T;T;T;T;T
Polyphen
0.0020
B;B;B;.;.
Vest4
0.19
MutPred
0.18
.;Loss of glycosylation at P447 (P = 0.016);Loss of glycosylation at P447 (P = 0.016);.;.;
MVP
0.55
MPC
0.039
ClinPred
0.29
T
GERP RS
3.8
Varity_R
0.15
gMVP
0.59

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: rs772810347; hg19: chr3-25773881; API