rs765145201

Variant names:

• chr3-25720032-G-A
• rs765145201
• NM_018297.4:c.1771C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-25720032-G-A
• chr3-25720032-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_018297.4(NGLY1):​c.1771C>T​(p.Gln591*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. Q591Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NGLY1 NM_018297.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.80
• 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, G2P, Labcorp Genetics (formerly Invitae)
• NGLY1-deficiency

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 11 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-25720032-G-A is Pathogenic according to our data. Variant chr3-25720032-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 1070987.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1771C>T	p.Gln591*	stop_gained	Exon 11 of 12	NP_060767.2
	NGLY1	NM_001145293.2		c.1717C>T	p.Gln573*	stop_gained	Exon 11 of 12	NP_001138765.1	Q96IV0-2
	NGLY1	NM_001145294.2		c.1645C>T	p.Gln549*	stop_gained	Exon 11 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.1771C>T	p.Gln591*	stop_gained	Exon 11 of 12	ENSP00000280700.5	Q96IV0-1
	NGLY1	ENST00000428257.5	TSL:1	c.1717C>T	p.Gln573*	stop_gained	Exon 11 of 12	ENSP00000387430.1	Q96IV0-2
	NGLY1	ENST00000308710.9	TSL:1	c.1708C>T	p.Gln570*	stop_gained	Exon 11 of 12	ENSP00000307980.5	A0A0C4DFP4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

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
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	37
DANN	Benign	0.91
Eigen	Benign	-0.088
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.26	N
PhyloP100		1.8
Vest4		0.27
GERP RS		2.9
Mutation Taster		=20/180	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.21		Position offset: -18

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs765145201; hg19: chr3-25761523;