3-25720032-G-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018297.4(NGLY1):c.1771C>G(p.Gln591Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Q591Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

NGLY1
NM_018297.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.80

Publications

1 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, G2P, Labcorp Genetics (formerly Invitae)
NGLY1-deficiency
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

NGLY1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08793807).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NGLY1	NM_018297.4	MANE Select	c.1771C>G	p.Gln591Glu	missense	Exon 11 of 12	NP_060767.2
NGLY1	NM_001145293.2		c.1717C>G	p.Gln573Glu	missense	Exon 11 of 12	NP_001138765.1	Q96IV0-2
NGLY1	NM_001145294.2		c.1645C>G	p.Gln549Glu	missense	Exon 11 of 12	NP_001138766.1	Q96IV0-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NGLY1	ENST00000280700.10	TSL:1 MANE Select	c.1771C>G	p.Gln591Glu	missense	Exon 11 of 12	ENSP00000280700.5	Q96IV0-1
NGLY1	ENST00000428257.5	TSL:1	c.1717C>G	p.Gln573Glu	missense	Exon 11 of 12	ENSP00000387430.1	Q96IV0-2
NGLY1	ENST00000308710.9	TSL:1	c.1708C>G	p.Gln570Glu	missense	Exon 11 of 12	ENSP00000307980.5	A0A0C4DFP4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000319

AC:

AN:

250834

AF XY:

0.0000369

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000232

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:

0.00000548

AC:

AN:

1460526

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726532

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.000179

AC:

AN:

44674

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00

AC:

AN:

86034

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111176

Other (OTH)

AF:

0.00

AC:

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000330

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital disorder of deglycosylation (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.70

CADD

Benign

(source)

DANN

Benign

0.17

DEOGEN2

Benign

0.074

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.28

M_CAP

Benign

0.0070

MetaRNN

Benign

0.088

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.99

PhyloP100

1.8

PrimateAI

Benign

0.18

PROVEAN

Benign

-0.59

REVEL

Benign

0.088

Sift

Benign

0.87

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.049

MutPred

0.69

Gain of disorder (P = 0.084)

MVP

0.28

MPC

0.038

ClinPred

0.016

GERP RS

2.9

Varity_R

0.028

gMVP

0.21

Mutation Taster

=92/8

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over