rs745814294

Positions:

• chr3-25737407-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_018297.4(NGLY1):​c.930C>T​(p.Gly310Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: NGLY1 NM_018297.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 O:1
• Conservation: PhyloP100: 0.510

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-25737407-G-A is Pathogenic according to our data. Variant chr3-25737407-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 221583.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, not_provided=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NGLY1	NM_018297.4	c.930C>T	p.Gly310Gly	synonymous_variant	6/12	ENST00000280700.10	NP_060767.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NGLY1	ENST00000280700.10	c.930C>T	p.Gly310Gly	synonymous_variant	6/12	1	NM_018297.4	ENSP00000280700.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 251018 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135656

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461656 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital disorder of deglycosylation Pathogenic:2 Uncertain:1 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 25, 2024	Variant summary: NGLY1 c.930C>T alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: One predicts the variant strengthens a cryptic 3' acceptor site and two predict the variant creates this site. Publications report experimental evidence that this variant affects mRNA splicing (Wai_2020, Hirayama_2022). The variant allele was found at a frequency of 8e-06 in 251018 control chromosomes (gnomAD). c.930C>T has been reported in the literature in individuals affected with Congenital Disorder Of Deglycosylation who were compound heterozygous with a pathogenic variant (He_2015, Lam_2017). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Hirayama_2022). The compound heterozygous patients showed severely reduced NGLA1 activity compared to the parent who carried p.Gln208Ter, and no activity was detected using a recombinant protein that is expected to result from the splicing alteration. The following publications have been ascertained in the context of this evaluation (PMID: 25900930, 27388694, 32123317, 34939090). ClinVar contains an entry for this variant (Variation ID: 221583). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Medical Biochemical Genetics, National Human Genome institute, NIH, National Institutes of Health	Jan 07, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	Splice site variant. Mild impairment -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 19, 2022	This sequence change affects codon 310 of the NGLY1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NGLY1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in the loss of 25 amino acid residue(s), but is expected to preserve the integrity of the reading-frame. This variant is present in population databases (rs745814294, gnomAD 0.002%). This variant has been observed in individual(s) with NGLY1-related conditions (PMID: 25900930). ClinVar contains an entry for this variant (Variation ID: 221583). Studies have shown that this variant results in the activation of a cryptic splice site in exon 6 (PMID: 32123317). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.97		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs745814294; hg19: chr3-25778898; COSMIC: COSV99770460; COSMIC: COSV99770460;