rs112237307

chr3-25729165-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_018297.4(NGLY1):c.1579A>G(p.Ile527Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,539,154 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (1 hom.)
• Consequence: NGLY1 NM_018297.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0220

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010139227).
• BP6: Variant 3-25729165-T-C is Benign according to our data. Variant chr3-25729165-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 474214.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 = 0.0015 (229/152260) while in subpopulation AFR AF= 0.00527 (219/41570). AF 95% confidence interval is 0.0047. There are 2 homozygotes in gnomad4. There are 119 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.1579A>G	p.Ile527Val	missense_variant	10/12	ENST00000280700.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NGLY1	ENST00000280700.10	c.1579A>G	p.Ile527Val	missense_variant	10/12	1	NM_018297.4	P1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152142 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00514

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.000479

GnomAD3 exomes AF: 0.000407 AC: 91 AN: 223324 Hom.: 0 AF XY: 0.000329 AC XY: 40 AN XY: 121568

Gnomad AFR exome AF: 0.00569

Gnomad AMR exome AF: 0.000360

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.0000191

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000134 AC: 186 AN: 1386894 Hom.: 1 Cov.: 30 AF XY: 0.000124 AC XY: 85 AN XY: 687844

Gnomad4 AFR exome AF: 0.00488

Gnomad4 AMR exome AF: 0.000390

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000271

Gnomad4 SAS exome AF: 0.0000272

Gnomad4 FIN exome AF: 0.0000197

Gnomad4 NFE exome AF: 0.00000374

Gnomad4 OTH exome AF: 0.000212

GnomAD4 genome AF: 0.00150 AC: 229 AN: 152260 Hom.: 2 Cov.: 32 AF XY: 0.00160 AC XY: 119 AN XY: 74458

Gnomad4 AFR AF: 0.00527

Gnomad4 AMR AF: 0.000524

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000274 Hom.: 1

Bravo AF: 0.00167

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000552 AC: 67

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital disorder of deglycosylation Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 08, 2021

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	14
Dann	Benign	0.96
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.33	N
LIST_S2	Benign	0.84	T;T;D;T;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.010	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.17	N;N;N;N;N
REVEL	Benign	0.098
Sift	Benign	0.16	T;T;T;T;T
Sift4G	Benign	0.66	T;T;T;T;T
Polyphen		0.0030	B;B;B;.;.
Vest4		0.13
MVP		0.39
MPC		0.033
ClinPred		0.0062	T
GERP RS		4.6
Varity_R		0.054
gMVP		0.28

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: rs112237307; hg19: chr3-25770656;