chr3-25739730-T-C

Variant names:

• chr3-25739730-T-C
• rs1553654596
• NM_018297.4:c.728A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_018297.4(NGLY1):​c.728A>G​(p.His243Arg) 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. 16/22 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. H243Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NGLY1 NM_018297.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.69
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_018297.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09672958).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NGLY1	NM_018297.4	c.728A>G	p.His243Arg	missense_variant	Exon 5 of 12	ENST00000280700.10	NP_060767.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NGLY1	ENST00000280700.10	c.728A>G	p.His243Arg	missense_variant	Exon 5 of 12	1	NM_018297.4	ENSP00000280700.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	16
DANN	Benign	0.20
DEOGEN2	Benign	0.11	.;T;.;T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.74	T;T;T;T;T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.097	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.51	N;N;N;.;.
PhyloP100		1.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.020	N;N;N;N;N
REVEL	Benign	0.020
Sift	Benign	0.75	T;T;T;T;T
Sift4G	Benign	0.79	T;T;T;T;T
Polyphen		0.0	B;B;B;.;.
Vest4		0.26
MutPred		0.43		Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);Gain of MoRF binding (P = 0.0309);.;.;
MVP		0.30
MPC		0.041
ClinPred		0.096	T
GERP RS		3.2
Varity_R		0.039
gMVP		0.41
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs1553654596; hg19: chr3-25781221;