Genetic Variant NM_018297.4:c.1604G>C (chr3-25729140-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_018297.4(NGLY1):c.1604G>C(p.Trp535Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000745 in 1,342,546 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 7.4e-7 ( 0 hom. )

Consequence

NGLY1
NM_018297.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.28

Publications

9 publications found

Variant links:

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

NGLY1 links:

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ACMG classification

Classification was made for transcript

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, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NGLY1	NM_018297.4 link	c.1604G>C	p.Trp535Ser	missense_variant	Exon 10 of 12	ENST00000280700.10	NP_060767.2	Q96IV0-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NGLY1	ENST00000280700.10 link	c.1604G>C	p.Trp535Ser	missense_variant	Exon 10 of 12	1	NM_018297.4	ENSP00000280700.5		Q96IV0-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000478

AC:

AN:

209102

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

7.45e-7

AC:

AN:

1342546

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

662300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29404

American (AMR)

AF:

0.00

AC:

AN:

34776

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22864

East Asian (EAS)

AF:

0.00

AC:

AN:

35362

South Asian (SAS)

AF:

0.0000151

AC:

AN:

66050

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49434

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5322

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1044830

Other (OTH)

AF:

0.00

AC:

AN:

54504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.18

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

.;T;.;T;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.93

D;D;D;D;D

M_CAP

Uncertain

0.11

MetaRNN

Pathogenic

0.88

D;D;D;D;D

MetaSVM

Benign

-0.54

MutationAssessor

Pathogenic

3.2

.;M;M;.;.

PhyloP100

7.3

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-14

D;D;D;D;D

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;D;D;D;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

1.0

D;D;D;.;.

Vest4

0.67

MutPred

0.56

.;Gain of disorder (P = 0.011);Gain of disorder (P = 0.011);.;.;

MVP

0.74

MPC

0.32

ClinPred

1.0

GERP RS

5.8

Varity_R

0.98

gMVP

0.90

Mutation Taster

=15/85

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over