Genetic Variant NM_018297.4:c.78G>T (chr3-25783313-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_018297.4(NGLY1):c.78G>T(p.Glu26Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NGLY1
NM_018297.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.484

Publications

0 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 links:

OXSM (HGNC:26063): (3-oxoacyl-ACP synthase, mitochondrial) This gene encodes a beta-ketoacyl synthetase. The encoded enzyme is required for elongation of fatty acid chains in the mitochondria. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2009]

OXSM links:

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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=0.15365061).

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.78G>T	p.Glu26Asp	missense	Exon 1 of 12	NP_060767.2
NGLY1	NM_001145293.2		c.78G>T	p.Glu26Asp	missense	Exon 1 of 12	NP_001138765.1	Q96IV0-2
NGLY1	NM_001145295.2		c.78G>T	p.Glu26Asp	missense	Exon 1 of 11	NP_001138767.1	Q96IV0-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NGLY1	ENST00000280700.10	TSL:1 MANE Select	c.78G>T	p.Glu26Asp	missense	Exon 1 of 12	ENSP00000280700.5	Q96IV0-1
NGLY1	ENST00000428257.5	TSL:1	c.78G>T	p.Glu26Asp	missense	Exon 1 of 12	ENSP00000387430.1	Q96IV0-2
NGLY1	ENST00000308710.9	TSL:1	c.69G>T	p.Glu23Asp	missense	Exon 1 of 12	ENSP00000307980.5	A0A0C4DFP4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1453070

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722346

African (AFR)

AF:

0.00

AC:

AN:

32788

American (AMR)

AF:

0.00

AC:

AN:

43938

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25782

East Asian (EAS)

AF:

0.00

AC:

AN:

39038

South Asian (SAS)

AF:

0.00

AC:

AN:

84952

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5488

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108704

Other (OTH)

AF:

0.00

AC:

AN:

60022

GnomAD4 genome

Cov.:

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

0.12

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.10

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.32

LIST_S2

Benign

0.66

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.95

PhyloP100

-0.48

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-0.60

REVEL

Benign

0.067

Sift

Benign

0.32

Sift4G

Benign

0.70

Polyphen

0.0

Vest4

0.12

MutPred

0.54

Loss of glycosylation at P25 (P = 0.0268)

MVP

0.29

MPC

0.034

ClinPred

0.24

GERP RS

1.7

PromoterAI

0.076

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.28

gMVP

0.29

Mutation Taster

=84/16

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over