rs748862974

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_018297.4(NGLY1):c.659G>A(p.Gly220Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000497 in 1,611,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

NGLY1
NM_018297.4 missense, splice_region

Scores

Splicing: ADA: 0.2399

Clinical Significance

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

Conservation

PhyloP100: 1.58

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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.059244603).

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
NGLY1	NM_018297.4	MANE Select	c.659G>A	p.Gly220Asp	missense splice_region	Exon 5 of 12	NP_060767.2
NGLY1	NM_001145293.2		c.659G>A	p.Gly220Asp	missense splice_region	Exon 5 of 12	NP_001138765.1
NGLY1	NM_001145294.2		c.533G>A	p.Gly178Asp	missense splice_region	Exon 5 of 12	NP_001138766.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NGLY1	ENST00000280700.10	TSL:1 MANE Select	c.659G>A	p.Gly220Asp	missense splice_region	Exon 5 of 12	ENSP00000280700.5
NGLY1	ENST00000428257.5	TSL:1	c.659G>A	p.Gly220Asp	missense splice_region	Exon 5 of 12	ENSP00000387430.1
NGLY1	ENST00000308710.9	TSL:1	c.650G>A	p.Gly217Asp	missense splice_region	Exon 5 of 12	ENSP00000307980.5

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000725

AC:

AN:

248142

AF XY:

0.0000744

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000379

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000425

AC:

AN:

1458968

Hom.:

Cov.:

AF XY:

0.0000468

AC XY:

AN XY:

725844

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33366

American (AMR)

AF:

0.000292

AC:

AN:

44530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.00

AC:

AN:

86040

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000414

AC:

AN:

1110576

Other (OTH)

AF:

0.0000498

AC:

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.000118

AC:

AN:

152114

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41406

American (AMR)

AF:

0.000655

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

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:

0.0000568

Hom.:

Bravo

AF:

0.0000831

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital disorder of deglycosylation

Uncertain:2

Oct 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 220 of the NGLY1 protein (p.Gly220Asp). This variant is present in population databases (rs748862974, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with NGLY1-related conditions. ClinVar contains an entry for this variant (Variation ID: 571965). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Inborn genetic diseases

Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.659G>A (p.G220D) alteration is located in exon 5 (coding exon 5) of the NGLY1 gene. This alteration results from a G to A substitution at nucleotide position 659, causing the glycine (G) at amino acid position 220 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.14

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.085

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.81

M_CAP

Benign

0.0093

MetaRNN

Benign

0.059

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

1.6

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.0

REVEL

Benign

0.049

Sift

Benign

0.29

Sift4G

Benign

0.42

Polyphen

0.0040

Vest4

0.32

MutPred

0.43

Gain of ubiquitination at K216 (P = 0.039)

MVP

0.33

MPC

0.043

ClinPred

0.081

GERP RS

4.5

Varity_R

0.078

gMVP

0.38

Mutation Taster

=78/22

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.24

dbscSNV1_RF

Benign

0.51

SpliceAI score (max)

0.11

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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over