3-25729140-C-T

Variant names:

• chr3-25729140-C-T
• rs767388144
• NM_018297.4:c.1604G>A

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_018297.4(NGLY1):​c.1604G>A​(p.Trp535*) variant causes a stop gained change involving the alteration of a 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NGLY1 NM_018297.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.28
• Publications: 9 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-25729140-C-T is Pathogenic according to our data. Variant chr3-25729140-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 221577.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGLY1	NM_018297.4	MANE Select	c.1604G>A	p.Trp535*	stop_gained	Exon 10 of 12	NP_060767.2
	NGLY1	NM_001145293.2		c.1550G>A	p.Trp517*	stop_gained	Exon 10 of 12	NP_001138765.1
	NGLY1	NM_001145294.2		c.1478G>A	p.Trp493*	stop_gained	Exon 10 of 12	NP_001138766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGLY1	ENST00000280700.10	TSL:1 MANE Select	c.1604G>A	p.Trp535*	stop_gained	Exon 10 of 12	ENSP00000280700.5
	NGLY1	ENST00000428257.5	TSL:1	c.1550G>A	p.Trp517*	stop_gained	Exon 10 of 12	ENSP00000387430.1
	NGLY1	ENST00000308710.9	TSL:1	c.1541G>A	p.Trp514*	stop_gained	Exon 10 of 12	ENSP00000307980.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1342546 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 662300

African (AFR) AF: 0.00 AC: 0 AN: 29404

American (AMR) AF: 0.00 AC: 0 AN: 34776

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22864

East Asian (EAS) AF: 0.00 AC: 0 AN: 35362

South Asian (SAS) AF: 0.00 AC: 0 AN: 66050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49434

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5322

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1044830

Other (OTH) AF: 0.00 AC: 0 AN: 54504

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Congenital disorder of deglycosylation (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	42
DANN	Uncertain	1.0
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.3
Vest4		0.19
GERP RS		5.8
Mutation Taster		=0/200	disease causing (ClinVar)

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: -7

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

Other links and lift over

dbSNP: rs767388144; hg19: chr3-25770631;