rs1553666033

Variant names:

• chr3-25783351-AC-A
• rs1553666033
• NM_018297.4:c.39delG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_018297.4(NGLY1):​c.39delG​(p.Ser14ProfsTer91) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000211 in 1,419,600 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. A13A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NGLY1 NM_018297.4 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 0.677
• Publications: 0 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]

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]

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 104 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-25783351-AC-A is Pathogenic according to our data. Variant chr3-25783351-AC-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 521914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NGLY1	NM_018297.4	c.39delG	p.Ser14ProfsTer91	frameshift_variant	Exon 1 of 12	ENST00000280700.10	NP_060767.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NGLY1	ENST00000280700.10	c.39delG	p.Ser14ProfsTer91	frameshift_variant	Exon 1 of 12	1	NM_018297.4	ENSP00000280700.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000211 AC: 3 AN: 1419600 Hom.: 0 Cov.: 34 AF XY: 0.00000284 AC XY: 2 AN XY: 703016

African (AFR) AF: 0.00 AC: 0 AN: 31524

American (AMR) AF: 0.0000260 AC: 1 AN: 38480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25046

East Asian (EAS) AF: 0.00 AC: 0 AN: 36964

South Asian (SAS) AF: 0.00 AC: 0 AN: 81874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4650

European-Non Finnish (NFE) AF: 0.00000183 AC: 2 AN: 1092702

Other (OTH) AF: 0.00 AC: 0 AN: 58806

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Jul 13, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital disorder of deglycosylation Pathogenic:1

Nov 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser14Profs*91) in the NGLY1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NGLY1 are known to be pathogenic (PMID: 24651605). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NGLY1-related conditions. ClinVar contains an entry for this variant (Variation ID: 521914). For these reasons, this variant has been classified as Pathogenic. -

Congenital disorder of deglycosylation 1 Pathogenic:1

Jan 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.68
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1553666033; hg19: chr3-25824842;