rs369598638

Positions:

• chr3-25732476-A-G
• chr3-25732476-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000280700.10(NGLY1):​c.1268T>C​(p.Leu423Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,322 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. L423Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NGLY1 ENST00000280700.10 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45

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]

ACMG classification

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=0.09482157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NGLY1	NM_018297.4	c.1268T>C	p.Leu423Pro	missense_variant	9/12	ENST00000280700.10	NP_060767.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NGLY1	ENST00000280700.10	c.1268T>C	p.Leu423Pro	missense_variant	9/12	1	NM_018297.4	ENSP00000280700	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250040 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135204

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: 0.0000464

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460322 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726446

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: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000283 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	20
DANN	Benign	0.94
DEOGEN2	Benign	0.12	.;T;.;T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.095	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	.;L;L;.;.
MutationTaster	Benign	1.0	D;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.050	N;N;N;N;N
REVEL	Benign	0.086
Sift	Benign	0.28	T;T;T;T;T
Sift4G	Benign	0.27	T;T;T;T;T
Polyphen		0.0090	B;B;B;.;.
Vest4		0.34
MutPred		0.48		.;Loss of stability (P = 0.0086);Loss of stability (P = 0.0086);.;.;
MVP		0.33
MPC		0.049
ClinPred		0.11	T
GERP RS		1.6
Varity_R		0.13
gMVP		0.76

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

Other links and lift over

dbSNP: rs369598638; hg19: chr3-25773967;