3-25739586-C-T

Variant names:

• chr3-25739586-C-T
• rs769627493
• NM_018297.4:c.872G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_018297.4(NGLY1):​c.872G>A​(p.Arg291Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,736 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R291L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: NGLY1 NM_018297.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71
• Publications: 2 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, G2P, Labcorp Genetics (formerly Invitae)
• NGLY1-deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_018297.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018297.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGLY1	NM_018297.4	MANE Select	c.872G>A	p.Arg291Gln	missense	Exon 5 of 12	NP_060767.2
	NGLY1	NM_001145293.2		c.872G>A	p.Arg291Gln	missense	Exon 5 of 12	NP_001138765.1	Q96IV0-2
	NGLY1	NM_001145294.2		c.746G>A	p.Arg249Gln	missense	Exon 5 of 12	NP_001138766.1	Q96IV0-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGLY1	ENST00000280700.10	TSL:1 MANE Select	c.872G>A	p.Arg291Gln	missense	Exon 5 of 12	ENSP00000280700.5	Q96IV0-1
	NGLY1	ENST00000428257.5	TSL:1	c.872G>A	p.Arg291Gln	missense	Exon 5 of 12	ENSP00000387430.1	Q96IV0-2
	NGLY1	ENST00000308710.9	TSL:1	c.863G>A	p.Arg288Gln	missense	Exon 5 of 12	ENSP00000307980.5	A0A0C4DFP4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 250892 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727168

African (AFR) AF: 0.0000597 AC: 2 AN: 33476

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111922

Other (OTH) AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital disorder of deglycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.91	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.7
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.87
Sift	Benign	0.10	T
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.80		Loss of catalytic residue at R291 (P = 0.0442)
MVP		0.99
MPC		0.28
ClinPred		0.95	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.83
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs769627493; hg19: chr3-25781077;