rs138477428

Variant names:

• chr3-25729184-G-A
• rs138477428
• NM_018297.4:c.1560C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-25729184-G-A
• chr3-25729184-G-T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_018297.4(NGLY1):​c.1560C>T​(p.Gly520Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000642 in 1,548,830 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). Synonymous variant affecting the same amino acid position (i.e. G520G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00067 (0 hom.)
• Consequence: NGLY1 NM_018297.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 1.41
• Publications: 1 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, Labcorp Genetics (formerly Invitae), G2P
• NGLY1-deficiency

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant 3-25729184-G-A is Benign according to our data. Variant chr3-25729184-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 474213.
• BP7: Synonymous conserved (PhyloP=1.41 with no splicing effect.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGLY1	NM_018297.4	MANE Select	c.1560C>T	p.Gly520Gly	synonymous	Exon 10 of 12	NP_060767.2
	NGLY1	NM_001145293.2		c.1506C>T	p.Gly502Gly	synonymous	Exon 10 of 12	NP_001138765.1
	NGLY1	NM_001145294.2		c.1434C>T	p.Gly478Gly	synonymous	Exon 10 of 12	NP_001138766.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NGLY1	ENST00000280700.10	TSL:1 MANE Select	c.1560C>T	p.Gly520Gly	synonymous	Exon 10 of 12	ENSP00000280700.5
	NGLY1	ENST00000428257.5	TSL:1	c.1506C>T	p.Gly502Gly	synonymous	Exon 10 of 12	ENSP00000387430.1
	NGLY1	ENST00000308710.9	TSL:1	c.1497C>T	p.Gly499Gly	synonymous	Exon 10 of 12	ENSP00000307980.5

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 151996 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000314

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: 0.000603

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000298 AC: 68 AN: 228448 AF XY: 0.000258

Gnomad AFR exome AF: 0.000435

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000633

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000510

Gnomad OTH exome AF: 0.000185

GnomAD4 exome AF: 0.000674 AC: 941 AN: 1396834 Hom.: 0 Cov.: 30 AF XY: 0.000657 AC XY: 456 AN XY: 693792

African (AFR) AF: 0.000193 AC: 6 AN: 31066

American (AMR) AF: 0.000200 AC: 8 AN: 40068

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24308

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 37018

South Asian (SAS) AF: 0.00 AC: 0 AN: 75384

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50976

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5540

European-Non Finnish (NFE) AF: 0.000831 AC: 894 AN: 1075438

Other (OTH) AF: 0.000561 AC: 32 AN: 57036

GnomAD4 genome AF: 0.000355 AC: 54 AN: 151996 Hom.: 0 Cov.: 32 AF XY: 0.000337 AC XY: 25 AN XY: 74224

African (AFR) AF: 0.000314 AC: 13 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15246

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

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

European-Non Finnish (NFE) AF: 0.000603 AC: 41 AN: 67984

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000374

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital disorder of deglycosylation (1)
-	-	1	NGLY1-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	10
DANN	Benign	0.64
PhyloP100		1.4

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs138477428; hg19: chr3-25770675;