3-25729275-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_018297.4(NGLY1):c.1469C>T(p.Ser490Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000316 in 1,489,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. S490S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

NGLY1
NM_018297.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 1.69

Publications

2 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: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.07246971).

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.1469C>T	p.Ser490Phe	missense	Exon 10 of 12	NP_060767.2
NGLY1	NM_001145293.2		c.1415C>T	p.Ser472Phe	missense	Exon 10 of 12	NP_001138765.1	Q96IV0-2
NGLY1	NM_001145294.2		c.1343C>T	p.Ser448Phe	missense	Exon 10 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.1469C>T	p.Ser490Phe	missense	Exon 10 of 12	ENSP00000280700.5	Q96IV0-1
NGLY1	ENST00000428257.5	TSL:1	c.1415C>T	p.Ser472Phe	missense	Exon 10 of 12	ENSP00000387430.1	Q96IV0-2
NGLY1	ENST00000308710.9	TSL:1	c.1406C>T	p.Ser469Phe	missense	Exon 10 of 12	ENSP00000307980.5	A0A0C4DFP4

Frequencies

GnomAD3 genomes

AF:

0.0000658

AC:

AN:

151988

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000958

GnomAD2 exomes

AF:

0.0000486

AC:

AN:

205898

AF XY:

0.0000622

show subpopulations

Gnomad AFR exome

AF:

0.000398

Gnomad AMR exome

AF:

0.0000413

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000408

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000269

AC:

AN:

1337446

Hom.:

Cov.:

AF XY:

0.0000318

AC XY:

AN XY:

660430

show subpopulations

African (AFR)

AF:

0.000546

AC:

AN:

29312

American (AMR)

AF:

0.0000862

AC:

AN:

34822

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22944

East Asian (EAS)

AF:

0.00

AC:

AN:

34904

South Asian (SAS)

AF:

0.00

AC:

AN:

64490

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48854

Middle Eastern (MID)

AF:

0.000378

AC:

AN:

5296

European-Non Finnish (NFE)

AF:

0.00000575

AC:

AN:

1042786

Other (OTH)

AF:

0.000167

AC:

AN:

54038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

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

AF:

0.0000723

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41512

American (AMR)

AF:

0.00

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67958

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000583

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000741

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital disorder of deglycosylation (2)

Congenital disorder of deglycosylation 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

Eigen

Benign

0.16

Eigen_PC

Benign

0.18

FATHMM_MKL

Benign

0.52

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.015

MetaRNN

Benign

0.072

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.6

PhyloP100

1.7

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.7

REVEL

Benign

0.10

Sift

Benign

0.036

Sift4G

Uncertain

0.048

Polyphen

0.72

Vest4

0.30

MVP

0.55

MPC

0.067

ClinPred

0.19

GERP RS

4.0

Varity_R

0.10

gMVP

0.54

Mutation Taster

=90/10

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over