rs139134926

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_018297.4(NGLY1):c.1508G>A(p.Arg503His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,554,868 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R503G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00015 ( 0 hom. )

Consequence

NGLY1
NM_018297.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.305

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

NGLY1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0040923357).

BP6

Variant 3-25729236-C-T is Benign according to our data. Variant chr3-25729236-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 541259.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00137 (209/152134) while in subpopulation AFR AF = 0.00491 (204/41510). AF 95% confidence interval is 0.00436. There are 1 homozygotes in GnomAd4. There are 109 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NGLY1	NM_018297.4 link	c.1508G>A	p.Arg503His	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.1508G>A	p.Arg503His	missense_variant	Exon 10 of 12	1	NM_018297.4	ENSP00000280700.5		Q96IV0-1

Frequencies

GnomAD3 genomes

AF:

0.00136

AC:

207

AN:

152016

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00488

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000309

AC:

AN:

230070

AF XY:

0.000263

show subpopulations

Gnomad AFR exome

AF:

0.00440

Gnomad AMR exome

AF:

0.000236

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:

0.000371

GnomAD4 exome

AF:

0.000146

AC:

205

AN:

1402734

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

AN XY:

697058

show subpopulations

African (AFR)

AF:

0.00485

AC:

152

AN:

31310

American (AMR)

AF:

0.000270

AC:

AN:

40782

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24512

East Asian (EAS)

AF:

0.00

AC:

AN:

37182

South Asian (SAS)

AF:

0.0000520

AC:

AN:

76964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5564

European-Non Finnish (NFE)

AF:

0.0000130

AC:

AN:

1078012

Other (OTH)

AF:

0.000419

AC:

AN:

57306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00137

AC:

209

AN:

152134

Hom.:

Cov.:

AF XY:

0.00147

AC XY:

109

AN XY:

74364

show subpopulations

African (AFR)

AF:

0.00491

AC:

204

AN:

41510

American (AMR)

AF:

0.000196

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67964

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000547

Hom.:

Bravo

AF:

0.00159

ESP6500AA

AF:

0.00704

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000511

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 22, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 25344691) -

Nov 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NGLY1: BP4 -

Congenital disorder of deglycosylation

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.75

CADD

Benign

7.2

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.084

.;T;.;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.60

T;T;T;T;T

M_CAP

Benign

0.0063

MetaRNN

Benign

0.0041

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.35

.;N;N;.;.

PhyloP100

-0.30

PrimateAI

Benign

0.18

PROVEAN

Benign

-0.70

N;N;N;N;N

REVEL

Benign

0.069

Sift

Benign

0.23

T;T;T;T;T

Sift4G

Benign

0.29

T;T;T;T;T

Polyphen

0.0

B;B;B;.;.

Vest4

0.055

MVP

0.15

MPC

0.041

ClinPred

0.0042

GERP RS

-10

Varity_R

0.016

gMVP

0.32

Mutation Taster

=97/3

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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rs139134926

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over