rs1553649841

Positions:

• chr3-25719512-T-C

Variant summary

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

The NM_018297.4(NGLY1):​c.1913A>G​(p.Asn638Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NGLY1 NM_018297.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.896

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=0.09253812).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NGLY1	NM_018297.4	c.1913A>G	p.Asn638Ser	missense_variant	12/12	ENST00000280700.10	NP_060767.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NGLY1	ENST00000280700.10	c.1913A>G	p.Asn638Ser	missense_variant	12/12	1	NM_018297.4	ENSP00000280700	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital disorder of deglycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2021

This sequence change replaces asparagine with serine at codon 638 of the NGLY1 protein (p.Asn638Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with NGLY1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2024

The c.1913A>G (p.N638S) alteration is located in exon 12 (coding exon 12) of the NGLY1 gene. This alteration results from a A to G substitution at nucleotide position 1913, causing the asparagine (N) at amino acid position 638 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 16, 2019

Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.092	.;T;T;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.77	T;T;T;T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.093	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	.;M;.;.
MutationTaster	Benign	1.0	D;D;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Benign	0.049
Sift	Benign	0.29	T;T;T;T
Sift4G	Benign	0.68	T;T;T;T
Polyphen		0.0020	B;B;.;.
Vest4		0.063
MutPred		0.17		.;Gain of disorder (P = 0.0665);.;.;
MVP		0.50
MPC		0.032
ClinPred		0.27	T
GERP RS		3.2
Varity_R		0.038
gMVP		0.13

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: rs1553649841; hg19: chr3-25761003;