3-25733931-T-C

Variant names:

• chr3-25733931-T-C
• rs201337954
• NM_018297.4:c.1201A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018297.4(NGLY1):​c.1201A>G​(p.Arg401Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,602 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R401R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NGLY1 NM_018297.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.69
• Publications: 38 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGLY1	NM_018297.4	MANE Select	c.1201A>G	p.Arg401Gly	missense	Exon 8 of 12	NP_060767.2
	NGLY1	NM_001145293.2		c.1147A>G	p.Arg383Gly	missense	Exon 8 of 12	NP_001138765.1	Q96IV0-2
	NGLY1	NM_001145294.2		c.1075A>G	p.Arg359Gly	missense	Exon 8 of 12	NP_001138766.1	Q96IV0-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGLY1	ENST00000280700.10	TSL:1 MANE Select	c.1201A>G	p.Arg401Gly	missense	Exon 8 of 12	ENSP00000280700.5	Q96IV0-1
	NGLY1	ENST00000428257.5	TSL:1	c.1147A>G	p.Arg383Gly	missense	Exon 8 of 12	ENSP00000387430.1	Q96IV0-2
	NGLY1	ENST00000308710.9	TSL:1	c.1138A>G	p.Arg380Gly	missense	Exon 8 of 12	ENSP00000307980.5	A0A0C4DFP4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251186 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461602 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727104

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33464

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111862

Other (OTH) AF: 0.00 AC: 0 AN: 60386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000000315292), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.078	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.36	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		4.7
PrimateAI	Benign	0.46	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Uncertain	0.42
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.014	D
Polyphen		1.0	D
Vest4		0.78
MutPred		0.47		Loss of MoRF binding (P = 0.0248)
MVP		0.71
MPC		0.29
ClinPred		0.99	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.74
gMVP		0.85
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs201337954; hg19: chr3-25775422;