3-25783242-G-T

Variant names:

• chr3-25783242-G-T
• rs765031643
• NM_018297.4:c.131+18C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_018297.4(NGLY1):​c.131+18C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000313 in 1,277,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000031 (0 hom.)
• Consequence: NGLY1 NM_018297.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.55
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.131+18C>A		intron	N/A	NP_060767.2
	NGLY1	NM_001145293.2		c.131+18C>A		intron	N/A	NP_001138765.1	Q96IV0-2
	NGLY1	NM_001145294.2		c.6-4554C>A		intron	N/A	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.131+18C>A		intron	N/A	ENSP00000280700.5	Q96IV0-1
	NGLY1	ENST00000428257.5	TSL:1	c.131+18C>A		intron	N/A	ENSP00000387430.1	Q96IV0-2
	NGLY1	ENST00000308710.9	TSL:1	c.122+18C>A		intron	N/A	ENSP00000307980.5	A0A0C4DFP4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000313 AC: 4 AN: 1277526 Hom.: 0 Cov.: 27 AF XY: 0.00000312 AC XY: 2 AN XY: 642004

African (AFR) AF: 0.00 AC: 0 AN: 28832

American (AMR) AF: 0.00 AC: 0 AN: 43316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23546

East Asian (EAS) AF: 0.00 AC: 0 AN: 35430

South Asian (SAS) AF: 0.00 AC: 0 AN: 82624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48698

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4980

European-Non Finnish (NFE) AF: 0.00000418 AC: 4 AN: 957556

Other (OTH) AF: 0.00 AC: 0 AN: 52544

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.39
DANN	Benign	0.57
PhyloP100		-1.6
PromoterAI		-0.0010	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.22		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.22		Position offset: 3

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

Other links and lift over

dbSNP: rs765031643; hg19: chr3-25824733;