rs767388144

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr3-25729140-C-A
• chr3-25729140-C-G
• chr3-25729140-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_018297.4(NGLY1):​c.1604G>T​(p.Trp535Leu) variant causes a missense 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NGLY1 NM_018297.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.28
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87

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>T	p.Trp535Leu	missense	Exon 10 of 12	NP_060767.2
	NGLY1	NM_001145293.2		c.1550G>T	p.Trp517Leu	missense	Exon 10 of 12	NP_001138765.1
	NGLY1	NM_001145294.2		c.1478G>T	p.Trp493Leu	missense	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>T	p.Trp535Leu	missense	Exon 10 of 12	ENSP00000280700.5
	NGLY1	ENST00000428257.5	TSL:1	c.1550G>T	p.Trp517Leu	missense	Exon 10 of 12	ENSP00000387430.1
	NGLY1	ENST00000308710.9	TSL:1	c.1541G>T	p.Trp514Leu	missense	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

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-13	D
REVEL	Uncertain	0.52
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.54		Loss of MoRF binding (P = 0.0435)
MVP		0.68
MPC		0.33
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.95
gMVP		0.77
Mutation Taster		=12/88	disease causing

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: rs767388144; hg19: chr3-25770631;