rs74650888

chr3-25720081-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_018297.4(NGLY1):c.1722A>G(p.Gln574=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00235 in 1,613,902 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (7 hom.)
• Consequence: NGLY1 NM_018297.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.458

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 3-25720081-T-C is Benign according to our data. Variant chr3-25720081-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 381455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.458 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00133 (202/152274) while in subpopulation NFE AF= 0.00248 (169/68020). AF 95% confidence interval is 0.00218. There are 0 homozygotes in gnomad4. There are 93 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NGLY1	NM_018297.4	c.1722A>G	p.Gln574=	synonymous_variant	11/12	ENST00000280700.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NGLY1	ENST00000280700.10	c.1722A>G	p.Gln574=	synonymous_variant	11/12	1	NM_018297.4	P1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 202 AN: 152156 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00248

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00149 AC: 375 AN: 251226 Hom.: 1 AF XY: 0.00154 AC XY: 209 AN XY: 135778

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00273

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00245 AC: 3588 AN: 1461628 Hom.: 7 Cov.: 31 AF XY: 0.00239 AC XY: 1740 AN XY: 727122

Gnomad4 AFR exome AF: 0.000478

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00111

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.00302

Gnomad4 OTH exome AF: 0.00174

GnomAD4 genome AF: 0.00133 AC: 202 AN: 152274 Hom.: 0 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74454

Gnomad4 AFR AF: 0.000409

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00248

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00211 Hom.: 0

Bravo AF: 0.00138

EpiCase AF: 0.00295

EpiControl AF: 0.00332

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	NGLY1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 15, 2020	- -

Congenital disorder of deglycosylation Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	2.1
Dann	Benign	0.39

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

LitVar

Other links and lift over

dbSNP: rs74650888; hg19: chr3-25761572;