rs765211108

Variant names:

• chr3-25729207-TTTGA-T
• rs765211108
• NM_018297.4:c.1533_1536delTCAA

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.1533_1536delTCAA​(p.Asn511LysfsTer51) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000178 in 1,569,000 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: NGLY1 NM_018297.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.80
• Publications: 7 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-25729207-TTTGA-T is Pathogenic according to our data. Variant chr3-25729207-TTTGA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 548658.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.1533_1536delTCAA	p.Asn511LysfsTer51	frameshift	Exon 10 of 12	NP_060767.2
	NGLY1	NM_001145293.2		c.1479_1482delTCAA	p.Asn493LysfsTer51	frameshift	Exon 10 of 12	NP_001138765.1	Q96IV0-2
	NGLY1	NM_001145294.2		c.1407_1410delTCAA	p.Asn469LysfsTer51	frameshift	Exon 10 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.1533_1536delTCAA	p.Asn511LysfsTer51	frameshift	Exon 10 of 12	ENSP00000280700.5	Q96IV0-1
	NGLY1	ENST00000428257.5	TSL:1	c.1479_1482delTCAA	p.Asn493LysfsTer51	frameshift	Exon 10 of 12	ENSP00000387430.1	Q96IV0-2
	NGLY1	ENST00000308710.9	TSL:1	c.1470_1473delTCAA	p.Asn490LysfsTer51	frameshift	Exon 10 of 12	ENSP00000307980.5	A0A0C4DFP4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.0000170 AC: 4 AN: 235796 AF XY: 0.0000156

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: 0.0000277

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000191 AC: 27 AN: 1416872 Hom.: 0 AF XY: 0.0000170 AC XY: 12 AN XY: 704458

African (AFR) AF: 0.00 AC: 0 AN: 31786

American (AMR) AF: 0.0000240 AC: 1 AN: 41688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24900

East Asian (EAS) AF: 0.00 AC: 0 AN: 37842

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.0000230 AC: 25 AN: 1086212

Other (OTH) AF: 0.00 AC: 0 AN: 58004

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152128 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74310

African (AFR) AF: 0.00 AC: 0 AN: 41430

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Congenital disorder of deglycosylation (2)
2	-	-	Congenital disorder of deglycosylation 1 (2)
2	-	-	not provided (2)
1	-	-	Peripheral neuropathy;C3714756:Intellectual disability;na:Neuromotor delay (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=4/196	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: rs765211108; hg19: chr3-25770698;